rs397508462

Variant names:

• chr7-117606701-A-C
• rs397508462
• NM_000492.4:c.2936A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-117606701-A-C
• chr7-117606701-A-G
• chr7-117606701-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM5 PP2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.2936A>C​(p.Asp979Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000879 in 1,591,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D979V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4 O:1
• Conservation: PhyloP100: 8.62
• Publications: 26 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117606701-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 53603.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 7-117606701-A-C is Pathogenic according to our data. Variant chr7-117606701-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53602.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2936A>C	p.Asp979Ala	missense_variant	Exon 18 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.178-1712T>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2936A>C	p.Asp979Ala	missense_variant	Exon 18 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251154 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000834 AC: 12 AN: 1439644 Hom.: 0 Cov.: 27 AF XY: 0.00000836 AC XY: 6 AN XY: 717908

African (AFR) AF: 0.00 AC: 0 AN: 32994

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.000279 AC: 11 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 85792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091992

Other (OTH) AF: 0.00 AC: 0 AN: 59736

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:2 Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D979A variant (also known as c.2936A>C), located in coding exon 18 of the CFTR gene, results from an A to C substitution at nucleotide position 2936. The aspartic acid at codon 979 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been detected in three individuals who also carried the 5T variant. All three individuals had congenital bilateral absence of vas deferens (CBAVD) and one also had recurrent infections, a sweat chloride level of 55mM, and 75% forced expiratory volume (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77; Mak V et al. JAMA, 1999 Jun;281:2217-24). In one functional study, this alteration was analyzed as part of a complex allele (p.R347H-p.D979A). Authors found that the alteration lead to misprocessing of CFTR and was critical for proper chloride channel function. In addition, they found that the complex allele combination lead to a dramatic decrease in chloride current. (Clain J et al. J. Biol. Chem., 2001 Mar;276:9045-9). 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 the available evidence, the clinical significance of this alteration remains unclear. -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 979 of the CFTR protein (p.Asp979Ala). This variant is present in population databases (rs397508462, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 9272157, 9493456, 10376575, 32020786, 34782259, 35858753). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53602). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 11118444). This variant disrupts the p.Asp979 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9401110, 29805046). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 18, 2018

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. -

not provided Uncertain:2

Feb 05, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2936A>C; p.Asp979Ala variant (rs397508462) is reported in the literature in individuals affected with congenital absence of vas deferens who carry a mildly pathogenic variant in CFTR (Dork 1997, Mak 1999, Wilschanski 2006), but is also reported in individuals with pancreatitis who carry variants in other pancreatitis-associated genes (Zou 2018), and in a pair of twins with cystic fibrosis who carry two pathogenic CFTR variants on opposite chromosomes (Hojo 1997). Functional assays show that the p.Asp979Ala variant result in a mild defect (Clain 2001). The p.Asp979Ala variant is reported in the ClinVar database (Variation ID: 53602), and is found in the East Asian population with an allele frequency of 0.05% (9/18394 alleles) in the Genome Aggregation Database. The asparagine at codon 979 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. A different variant at this codon, p.Asp979Val, is reported as a CF-causing variant in the CFTR2 database (see CFTR2 database link). While the p.Asp979Ala variant is not predicted to cause classic cystic fibrosis, based on available information, the clinical significance is uncertain for CFTR-related disorders. References: CFTR2 database: https://cftr2.org/ Clain J et al. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J Biol Chem. 2001 Mar 23;276(12):9045-9. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. Hojo S et al. (Two cases of cystic fibrosis in Japanese/German twins). Nihon Kyobu Shikkan Gakkai Zasshi. 1997 Nov;35(11):1259-64. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999 Jun 16;281(23):2217-24. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. -

Jan 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15084988, 35119551, 21483833, 32777524, 30420730, 9272157, 32020786, 9493456, 34782259, 29997923, 32429104, 35858753, 26708955, 9550362, 22504961, 23820649, 9401110, 16840743, 12940920, 10376575, 20932301, 35313924, Bihler2023[Pre-print], 11118444) -

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

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Supporting+PM3+PM5+PP3+PP4 -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 12, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.2936A>C (p.Asp979Ala) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 3.5e-05 in 253874 control chromosomes (gnomAD and publications). c.2936A>C has been observed in multiple individuals affected with Congenital Bilateral Absence Of The Vas Deferens (CBAVD) who carry the variant in trans with the pathogenic 5T allele (e.g. Dork_1997, Mak_1999, Luo_2021). It has also been reported in the compound heterozygous state together with a pathogenic variant in at least two individuals with clinical features of CF, one with a classic CF diagnosis and the other with intermediate sweat chloride levels (e.g. Shen_2022, Zhou_2025). In addition, the variant was found in two twin siblings with CF who carried another pathogenic mutation (p.R347H) in cis and the common disease variant p.F508del on the other allele (Hojo_1998). It was speculated that the p.D979A variant contributes to a more severe disease phenotype in these individuals. Publications reporting experimental evidence evaluating an impact on protein function indicate that the variant results in a partial reduction of CFTR processing, moderate effects on chloride channel dynamics and has approximately 12% of normal chloride channel conductance relative to wild type (e.g. Clain_2001, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 15744523, 11118444, 9272157, 21483833, 15121783, 20932301, 9550362, 15537723, 19166122, 32777524, 10376575, 15084988, 24697796, 12940920, 35858753, 16840743, 39773272, 30420730). ClinVar contains an entry for this variant (Variation ID: 53602). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.
PhyloP100		8.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.5	D;.;.;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.98
MutPred		0.98		Loss of ubiquitination at K978 (P = 0.1601);.;.;.;.;
MVP		1.0
MPC		0.015
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397508462; hg19: chr7-117246755;