rs1800103

Positions:

chr7-117592588-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_000492.4(CFTR):c.2421A>G(p.Ile807Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000905 in 1,527,860 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 7 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:8

Conservation

PhyloP100: 0.357

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015308082).

BP6

Variant 7-117592588-A-G is Benign according to our data. Variant chr7-117592588-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35842.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=9, Pathogenic=1}. Variant chr7-117592588-A-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 7 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2421A>G	p.Ile807Met	missense_variant	14/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2421A>G	p.Ile807Met	missense_variant	14/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000774

AC:

139

AN:

179550

Hom.:

AF XY:

0.000970

AC XY:

AN XY:

94822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000251

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00520

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000623

Gnomad OTH exome

AF:

0.000486

GnomAD4 exome

AF:

0.000955

AC:

1314

AN:

1375492

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

737

AN XY:

677592

show subpopulations

Gnomad4 AFR exome

AF:

0.0000328

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00596

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000778

Gnomad4 OTH exome

AF:

0.000880

GnomAD4 genome

AF:

0.000446

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000786

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000877

AC:

106

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2018	This variant is associated with the following publications: (PMID: 29805046, 9736778, 24631642, 28194692, 20460946, 26708955, 17489851, 14998948, 17003641, 20977904, 19202204, 19812525, 25033378, 20722470, 23951356) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	The CFTR c.2421A>G; p.Ile807Met variant (rs1800103), is reported in the literature in the compound heterozygous state or in the heterozygous state with an unknown second allele in individuals affected with chronic pancreatitis (Danziger 2004, Keiles 2006, Masson 2013), cystic fibrosis (Behar 2017, Kolesar 2008, Schrijver 2016), and congenital bilateral absence of vas deferens (Vankeerberghen 1998). However, this variant has also been observed in equal numbers of control samples (LaRusch 2014, Makrythanasis 2010, Tzetis 2007). The variant is also reported in ClinVar (Variation ID: 35842). This variant is found in the South Asian population with an overall allele frequency of 0.52% (77/14800 alleles, including a single homozygote) in the Genome Aggregation Database. The isoleucine at codon 807 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.738). However, functional studies show no defects in protein maturation or chloride channel activity (Raraigh 2018, Vankeerberghen 1998). Due to conflicting information, the clinical significance of the p.Ile807Met variant is uncertain at this time. References: Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. PMID: 28546993. Danziger KL et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004 Mar;19(3):540-6. PMID: 14998948. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Kolesar P et al. Mutation analysis of the CFTR gene in Slovak cystic fibrosis patients by DHPLC and subsequent sequencing: identification of four novel mutations. Gen Physiol Biophys. 2008 Dec;27(4):299-305. PMID: 19202204. 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 Jul 17;10(7):e1004376. PMID: 25033378. Makrythanasis P et al. Cystic fibrosis conductance regulator, tumor necrosis factor, interferon alpha-10, interferon alpha-17, and interferon gamma genotyping as potential risk markers in pulmonary sarcoidosis pathogenesis in Greek patients. Genet Test Mol Biomarkers. 2010 Aug;14(4):577-84. PMID: 20722470. 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 Aug 8;8(8):e73522. PMID: 23951356. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046. Schrijver I et al. The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. J Mol Diagn. 2016 Jan;18(1):39-50. PMID: 26708955. Tzetis M et al. Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet. 2007 May;71(5):451-7. PMID: 17489851. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9. PMID: 9736778. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 10, 2022	- -

Cystic fibrosis

Uncertain:3Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 19, 2024	The p.I807M variant (also known as c.2421A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 2421. The isoleucine at codon 807 is replaced by methionine, an amino acid with highly similar properties. This variant was found to co-occur with a pathogenic mutation in CFTR and SPINK1 in an individual presenting with chronic pancreatitis (Schneider A et al. Gastroenterology, 2011 Jan;140:162-71). In a cohort of 253 French individuals with idiopathic chronic pancreatitis, two were identified as heterozygous for p.I807M; one was also heterozygous for p.R117H, phase uncertain (Masson E et al. PLoS ONE, 2013 Aug;8:e73522). Another study observed this variant in individuals with pancreatitis and healthy controls at the same frequency (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). Functional data demonstrated this variant displayed both maturation of the protein and chloride channel activity similar to that of wild-type protein (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077), although bicarbonate permeability and conductance, which are more relevant in the development of pancreatitis, were not assessed. 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, the clinical significance of this alteration remains unclear. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 05, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

CFTR-related disorder

Pathogenic:1Benign:1

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 02, 2024

Variant summary: CFTR c.2421A>G (p.Ile807Met) results in a conservative amino acid change located in the CFTR regulator domain (IPR025837) 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 0.00078 in 182610 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00078 vs 0.0063), allowing no conclusion about variant significance. c.2421A>G, has been reported in the literature in individuals affected with Idiopathic Chronic Pancreatitis (ICP) (Masson_2013) and healthy controls with comparable allele frequencies (LaRusch_2014). Multiple ICP patients reported with this variant also carried another disease variant in either CFTR or the CPANC causative gene SPINK1 (Masson_2013, Pelletier _2010, and Schneider_2011), indicating that the contribution of this particular variant to the etiology of pancreatitis is unlikely. In addition, multiple studies list this variant as neutral variant with no clinical consequence. (Fanen_2014, Castellani_2008). In toto, these data do not allow any conclusion about variant significance in the context of CF, CFTR-RD or chronic pancreatitis. At least 3 independent publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation. These results showed no damaging effect of this variant on CFTR maturation as well as chloride conductance (example, Vankeerberghen_1998, Raraigh_2018, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 28603918, 14998948, 24631642, 18716917, 17003641, 19202204, 25033378, 20722470, 23951356, 25651269, 20460946, 29805046, 20977904, 26708955, 17489851, 9736778, 26277102, 19812525, 38388235). ClinVar contains an entry for this variant (Variation ID: 35842). Based on the evidence outlined above, the variant in isolation was classified as likely benign. -

Hereditary pancreatitis

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

May 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;T;.

Eigen

Benign

0.0061

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.3

M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

N;.;N;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

D;.;D;.

Sift4G

Pathogenic

0.0010

D;.;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.80

MVP

1.0

MPC

0.0060

ClinPred

0.15

GERP RS

-4.5

Varity_R

0.42

gMVP

0.69

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over