7-117504290-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000492.4(CFTR):c.91C>T(p.Arg31Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,611,884 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (9 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:8
• Conservation: PhyloP100: 3.04

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 32 pathogenic changes around while only 4 benign (89%) in NM_000492.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011254132).
• BP6: Variant 7-117504290-C-T is Benign according to our data. Variant chr7-117504290-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35893.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=9}. Variant chr7-117504290-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.91C>T	p.Arg31Cys	missense_variant	2/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.91C>T	p.Arg31Cys	missense_variant	2/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00168 AC: 421 AN: 250938 Hom.: 1 AF XY: 0.00164 AC XY: 223 AN XY: 135608

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.00544

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00154 AC: 2241 AN: 1459662 Hom.: 9 Cov.: 29 AF XY: 0.00153 AC XY: 1112 AN XY: 726340

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.00702

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74420

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00483

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.00133

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00167 AC: 203

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:3 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Jul 26, 2023	This variant was classified based on the report of 1 patient with a clinically confirmed diagnosis of cystic fibrosis in the context of re-classifying variants in the German Cystic Fibrosis Registry (Muko e.V.). Patients have not been seen personally, but only reports were evaluated. Criteria applied:PP3, PM5_STR, BP6, BS3_SUP, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 09, 2019	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 26, 2023	The frequency of this variant in the general population, 0.0015 (191/128724 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with mild cystic fibrosis (CF) (PMID: 9272738 (1997)), pancreatitis (PMID: 12120234 (2001), 25033378 (2014), 25383785 (2015), 25492507 (2015), 25869325 (2015), 28544683 (2017)), and bronchiectasis (PMID: 7522211 (1994), 28544683 (2017), 29997923 (2018)). The variant has also been reported in unaffected individuals (PMID: 23514810 (2013), 25033378 (2014), 29997923 (2018)), including an unaffected individual in a homozygous state (PMID: 7522211 (1994)). The variant does not prevent chloride conduction by the CFTR protein in functional studies (PMID: 25824995 (2015)), but it has been reported as causing reduced CFTR protein activity by enhancing endocytosis of the CFTR protein (PMID: 16339147 (2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	The CFTR c.91C>T; p.Arg31Cys variant (rs1800073) is reported in individuals with idiopathic pancreatitis (Bernardino 2000, Gomez-Lira 2001), oligospermia (Gallati 2009), bronchiectasis (Guan 2018), mild pulmonary disorders (Ghanem 1994), and congenital absence of the vas deferens (Fang 2022). Although initial functional studies suggested a defect in CFTR processing and chloride transport activity (Jurkuvenaite 2006), subsequent studies indicated no defects (Sosnay 2013). In addition, the variant has been reported as a homozygote in an asymptomatic individual (Ghanem 1994) and was shown not to be enriched in individuals diagnosed with pancreatitis (LaRusch 2014). This variant is reported in ClinVar (Variation ID: 35893), and found in the general population with an overall allele frequency of 0.2% (447/276630 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.669). However, another variant at this codon (p.Arg31Leu) has been reported in an individual with elevated sweat chloride levels (Zielenski 1995) and exhibited 56% of wildtype chloride channel activity in functional assays (Raraigh 2018). Due to the conflicting information regarding this variant, its clinical significance is uncertain at this time. References: Bernardino AL et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000;4(1):69-74. PMID: 10794365 Fang J et al. Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations. Front Genet. 2022 Nov 9;13:1035468. PMID: 36437957. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. PMID: 20021716 Ghanem N et al. Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1994 May 15;21(2):434-6. PMID: 7522211 Gomez-Lira M et al. CFTR and cationic trypsinogen mutations in idiopathic pancreatitis and neonatal hypertrypsinemia. Pancreatology. 2001;1(5):538-42. PMID: 12120234 Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. PMID: 29997923 Jurkuvenaite A et al. Mutations in the amino terminus of the cystic fibrosis transmembrane conductance regulator enhance endocytosis. J Biol Chem. 2006 Feb 10;281(6):3329-34. PMID: 16339147 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 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 Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870 Zielenski J et al. Identification of six mutations (R31L, 441delA, 681delC, 1461ins4, W1089R, E1104X) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat. 1995;5(1):43-7. PMID: 7537150 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2018	- -

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2016	Variant summary: c.91C>T affects a conserved nucleotide, resulting in amino acid change from Arg to Cys. 5/5 in-silico tools predict damaging outcome. This variant was found in 214/124456 control chromosomes at a frequency of 0.0017195, including 1 homozygous occurrence. This frequency does not significantly exceed maximal expected frequency of a pathogenic allele (0.0129603) for non-classic CF. This variant has been found in patients with atypical CF, ICP and asthma-like bronchopathy. Variant was also found in healthy individuals, including 1 compound heterozygote with F508del with no symptoms suggestive of CF, 1 homozygous asymptomatic 6 y.o. child with family member presented with asthma-like bronchopathy (Ghanem_1994) and one homozygote in ExAC database. CFTR2 database classified this variant as non-CF-casuing based on clinical and functional data (Sosnay_2013). A case-control study including more than 2000 samples showed odds ratio of this variant associated with pancreatitis was 0.42, suggesting this variant does not increase the risk to develop pancreatitis (LaRusch_2014). Taken together, this variant was classified as Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2017	The R31C variant in the CFTR gene was first identified in the homozygous state in an asymptomatic individual and reported as a benign polymorphism (Ghanem et al., 1994). Other publications have reported this variant in association with disseminated bronchiectasis (Girodon et al., 1997), idiopathic pancreatitis (Gomez Lira et al., 2001), and oligospermia (Gallati et al., 2009), though a second CFTR variant was not identified in these cases. The R31C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R31C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R31L) was identified in an adult woman with pulmonary symptoms but normal pulmonary function, normal pancreatic function, and repeated abnormal sweat chloride levels (mean value 90.9 mmol/L); no second CFTR variant was identified (Zielenski et al., 1995). Functional studies performed show that R31C affects protein biogenesis, although the defect is not complete (Jurkuvenaite et al., 2006). While the R31C variant has been deemed not to be cystic fibrosis-causing (Sosnay et al., 2013), it is possible this variant may have reduced penetrance in association with CF-related disorders. We interpret R31C as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

- -

CFTR-related disorder Uncertain:1

Uncertain significance, 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). 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. -

Congenital bilateral aplasia of vas deferens from CFTR mutation Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 30, 2023

- -

Hereditary pancreatitis Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;.;.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.8	L;.;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N;.;.;N;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.012	D;.;.;D;.
Sift4G	Pathogenic	0.0010	D;.;.;D;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.89
MVP		0.99
MPC		0.0038
ClinPred		0.031	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.77

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

Other links and lift over

dbSNP: rs1800073; hg19: chr7-117144344; COSMIC: COSV50115848;