7-117610521-G-C

Variant names:

• chr7-117610521-G-C
• rs1800111
• NM_000492.4:c.2991G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.2991G>C​(p.Leu997Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,990 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L997L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (8 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:20 B:3 O:3
• Conservation: PhyloP100: 1.65
• Publications: 123 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• BP4: Computational evidence support a benign effect (MetaRNN=0.02057156).
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.2991G>C	p.Leu997Phe	missense splice_region	Exon 19 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.178-5532C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2991G>C	p.Leu997Phe	missense splice_region	Exon 19 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.2991G>C	p.Leu997Phe	missense splice_region	Exon 19 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.2901G>C	p.Leu967Phe	missense splice_region	Exon 18 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 320 AN: 151454 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00658

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00482

GnomAD2 exomes AF: 0.00229 AC: 576 AN: 251082 AF XY: 0.00244

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00420

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00260

Gnomad OTH exome AF: 0.00573

GnomAD4 exome AF: 0.00179 AC: 2617 AN: 1460462 Hom.: 8 Cov.: 31 AF XY: 0.00192 AC XY: 1398 AN XY: 726580

African (AFR) AF: 0.000359 AC: 12 AN: 33408

American (AMR) AF: 0.00455 AC: 203 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00571 AC: 149 AN: 26084

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.00140 AC: 121 AN: 86226

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53356

Middle Eastern (MID) AF: 0.00816 AC: 47 AN: 5762

European-Non Finnish (NFE) AF: 0.00169 AC: 1878 AN: 1111052

Other (OTH) AF: 0.00337 AC: 203 AN: 60294

GnomAD4 genome AF: 0.00211 AC: 320 AN: 151528 Hom.: 1 Cov.: 31 AF XY: 0.00212 AC XY: 157 AN XY: 73992

African (AFR) AF: 0.000436 AC: 18 AN: 41320

American (AMR) AF: 0.00657 AC: 100 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10338

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 67936

Other (OTH) AF: 0.00478 AC: 10 AN: 2092

Alfa AF: 0.00235 Hom.: 1

Bravo AF: 0.00262

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00209 AC: 254

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:20 Benign:3 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:9

Dec 27, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L997F variant in the CFTR gene has been reported previously in trans with another pathogenic CFTR variant in individuals with cystic fibrosis and atypical cystic fibrosis, as well as in asymptomatic individuals (Lucarelli et al., 2010; Strom et al., 2011; Schippa et al., 2013). It has been suggested that the presence of the R117L variant in cis with L997F as a complex allele may in part explain the variable phenotype observed in individuals with the L997F variant (Lucarelli et al., 2010). The L997F variant is observed in 59/10,146 (0.58%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The L997F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Functional studies demonstrated that the L997F variant was associated with somewhat reduced chloride transport (VanGoor et al., 2014). We interpret L997F as a variant of uncertain significance.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 12, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 07, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2991G>C (p.Leu997Phe) variant (also known as L997F) has been reported with other CFTR variants in the published literature in individuals affected with cystic fibrosis (PMIDs: 1379210 (1992), 9921909 (1998), 17572159 (2008), 20706124 (2010), 21804385 (2011), 23613805 (2013), 27738188 (2016), 38265526 (2024)) and CFTR-related disorders including pancreatitis (PMIDs: 10801389 (2000), 18501000 (2008), 20460946 (2010), 23951356 (2013), 29589582 (2018), 37389024 (2023)), bronchiectasis (PMID: 9921909 (1998)), and congenital bilateral absence of the vas deferens (CBAVD) (PMIDs: 9272157 (1997), 10875853 (2000), 26911355 (2016), 36446526 (2023)). This variant was also found to occur as part of a complex allele p.[R117L; L997F] and is often associated with a more severe phenotype in individuals with cystic fibrosis (PMIDs: 20706124 (2010), 25910067 (2015), 27738188 (2016)). This variant has also been reported in homozygous and compound heterozygous asymptomatic individuals (PMIDs: 12014388 (2002), 15857421 (2005), 20706124 (2010), 36238659 (2022) and CFTR France (https://cftr.iurc.montp.inserm.fr/cftr/)). Functional studies indicated that this variant causes significantly reduced chloride conductance to approximately 22% of the wild type that increases to 71% with ivacaftor treatment (PMIDs: 23974870 (2013), 23891399 (2014), 27738188 (2016), 34761808 (2021)) and reduces bicarbonate conductance (PMID: 25033378 (2014)). The frequency of this variant in the general population, 0.0099 (115/11590 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

Dec 16, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2991G>C; p.Leu997Phe variant (rs1800111) has been identified in multiple individuals diagnosed with CFTR-related disorders (Bergougnoux 2015, Gallati 2009, Gomez-Lira 2000, Hamoir 2013, Lucarelli 2010, Masson 2013, Pelletier 2010), but case control studies disagree if this variant is enriched in pancreatitis patients (LaRusch 2014, Gomez-Lira 2000). In addition, individuals homozygous for this variant have been reported to be clinically asymptomatic (Derichs 2005, Stanke 2008, Terlizzi 2017). Functional characterization of the variant protein indicates a reduction in the CFTR chloride transport activity (Bergougnoux 2015, Sosnay 2013, Van Goor 2014), but at a level unlikely to cause cystic fibrosis (Sosnay 2013, Strom 2011). This variant is reported in ClinVar (Variation ID: 7229) and is observed in the general population at a frequency of 0.22% (627/282,204 alleles, including 3 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.625). Due to the conflicting information regarding this variant, its clinical significance cannot be determined with certainty. References: Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015; 14(5):646-53. PMID: 25797027. Derichs N et al. Homozygosity for L997F in a child with normal clinical and chloride secretory phenotype provides evidence that this cystic fibrosis transmembrane conductance regulator mutation does not cause cystic fibrosis. Clin Genet. 2005; 67(6):529-31. PMID: 15857421. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. PMID: 20021716. Gomez-Lira M et al. High frequency of cystic fibrosis transmembrane regulator mutation L997F in patients with recurrent idiopathic pancreatitis and in newborns with hypertrypsinemia. Am J Hum Genet. 2000; 66(6):2013-4. PMID: 10801389. Hamoir C et al. Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. Digestion. 2013; 87(4):229-39. PMID: 23751316. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 10(7):e1004376. PMID: 25033378. Lucarelli M et al. A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation. Genet Med. 2010; 12(9):548-55. PMID: 20706124. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013; 8(8):e73522. PMID: 23951356. Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010; 10(2-3):158-64. PMID: 20460946. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. Stanke F et al. Diversity of the basic defect of homozygous CFTR mutation genotypes in humans. J Med Genet. 2008; 45(1):47-54. PMID: 18178635. Strom C et al. The dangers of including nonclassical cystic fibrosis variants in population-based screening panels: p.L997F, further genotype/phenotype correlation data. Genet Med. 2011; 13(12):1042-4. PMID: 21804385. Terlizzi V et al. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. J Med Genet. 2017 Apr;54(4):224-235. PMID: 27738188. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM3:Very Strong, PM2:Supporting, PS3:Supporting

Sep 26, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cystic fibrosis Pathogenic:1 Uncertain:6 Benign:1 Other:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L997F variant (also known as c.2991G>C), located in coding exon 19 of the CFTR gene, results from a G to C substitution at nucleotide position 2991. The leucine at codon 997 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration is known to occur in isolation or as part of a complex allele, p.[R117L;L997F], and it is associated with a range of clinical outcomes (Stanke F et al. J. Med. Genet., 2008 Jan;45:47-54; Lucarelli M et al. Genet Med, 2010 Sep;12:548-55; Strom CM et al. Genet Med, 2011 Dec;13:1042-4; Lucarelli M et al. Mol Med, 2015 Apr;21:257-75; Terlizzi V et al. J. Med. Genet., 2017 04;54:224-235). Some individuals homozygous for p.L997F or compound heterozygous with a second CFTR mutation were reported to be asymptomatic, whereas others had intermediate sweat chloride levels and exhibited CFTR-related disorders, including congenital bilateral absence of the vas deferens, pancreatitis, and bronchiectasis. In contrast, the p.[R117L;L997F] complex allele is associated with a more severe phenotype and has been described in multiple homozygous or compound heterozygous individuals with elevated sweat chloride level and cystic fibrosis. In functional studies, p.R117L was shown to retain normal CFTR maturation/processing, but result in approximately 20% of wild-type CFTR function (Sosnay PR et al. Nat Genet, 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis when it occurs in isolation; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance.

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Risk Factor and reported on 03-03-2021 by Breda Genetics. GenomeConnect-InvitaePIN assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

May 18, 2021

Pars Genome Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 14, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 22, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Dec 01, 2022

Eurofins-Biomnis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 05, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

CFTR-related disorder Pathogenic:2 Uncertain:2 Benign:1

Oct 29, 2021

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 14, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Obstructive azoospermia Pathogenic:1

Mar 16, 2022

Institute of Reproductive Genetics, University of Münster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pancreatitis Uncertain:1

Sep 15, 2015

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Infertility disorder Uncertain:1

MAGI's Lab - Research, MAGI Group

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 12, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.2991G>C (p.Leu997Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 254424 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0024 vs 0.013), allowing no conclusion about variant significance. c.2991G>C has been reported in the literature in patients with a wide range of atypical CFTR-related phenotypes such as bronchiectasis, pancreatitis, hypertrypsinemia, asthma, renal agenesis without a strong evidence of causality (example, Lebecque_2011, Tzetis_2001, Casals_2000, Padoan_2002); it is also found in ~ 1% of normal alleles from various studies. Of note, two homozygote individuals, one completely unaffected (Derichs_2005) and one only affected with allergic bronchopulmonary aspergillosis (ABPA) (Lebecque_2011) have been reported. The variant has also been found to be in cis with other CFTR deleterious variants such as deltaF508 (Fanen_1992), a large deletion spanning exons 2-9 of the CFTR gene (Schneider_2007, Strom_2011) and with R117L (Lucarelli_2010, classified as likely pathogenic) in CF patients supporting a benign outcome. Lastly, the variant has also been reported as having been co-inherited with a disease causing deletion spanning the entire SPINK1 gene in one family segregating with chronic pancreatitis (Masson_2007, cited in Bombieri_2011) supporting an alternative molecular basis of disease. These data indicate that the variant is unlikely to be associated with CF or any of its related variably expressive disease phenotypes. Reputed databases such as CFTR2 cite this variant as not disease causing (Sosnay_2013). In addition, functional studies suggest the variant could play a role in bicarbonate permeability relevant to organs in which CFTR is used for bicarbonate secretion (LaRush_2014) and has significantly reduced chloride conductance (Van Goor_2013), however the in vivo impact of these functional defects are unknown. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, at-least two other submitters report a benign/likely benign outcome. Based on the evidence outlined above, the variant in isolation was classified as benign for CF and associated phenotypes.

PANCREATITIS, IDIOPATHIC, SUSCEPTIBILITY TO Other:1

Jan 01, 2001

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

HYPERTRYPSINEMIA, NEONATAL, SUSCEPTIBILITY TO Other:1

Jan 01, 2001

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.63
Sift	Benign	0.053	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.73		Loss of stability (P = 0.2182)
MVP		1.0
MPC		0.0045
ClinPred		0.029	T
GERP RS		2.9
Varity_R		0.61
gMVP		0.93
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800111; hg19: chr7-117250575;