rs397508462
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000492.4(CFTR):āc.2936A>Cā(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
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2936A>C | p.Asp979Ala | missense_variant | 18/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2936A>C | p.Asp979Ala | missense_variant | 18/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.178-1712T>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251154Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135772
GnomAD4 exome AF: 0.00000834 AC: 12AN: 1439644Hom.: 0 Cov.: 27 AF XY: 0.00000836 AC XY: 6AN XY: 717908
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74454
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2018 | - - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | 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 individuals with clinical features of CFTR-related conditions (PMID: 9493456, 10376575, 32020786, 34782259). ClinVar contains an entry for this variant (Variation ID: 53602). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 07, 2024 | 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. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 253874 control chromosomes (gnomAD and publications). c.2936A>C has been reported in the literature 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). 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 may contribute to more severe disease in these individuals, however the contributions of the individual variants to the phenotype could not be determined. The variant was also detected in several individuals with pancreatitis, however co-occurred with variants in SPINK1 and PRSS1 (e.g. Zou_2018). At least one publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant results in a partial reduction of CFTR processing and moderate effects on chloride channel dynamics, consistent with the milder CFTR-related phenotype (CBAVD) that has been observed in most patients with the variant (e.g. Clain_2001). The following publications have been ascertained in the context of this evaluation (PMID: 15744523, 11118444, 9272157, 21483833, 15121783, 20932301, 9550362, 15537723, 19166122, 32777524, 10376575, 15084988, 24697796, 12940920, 16840743, 30420730, Lucarelli et al, 35858753).ClinVar contains an entry for this variant (Variation ID: 53602). Based on the evidence outlined above, the variant was classified as likely pathogenic in association with CBAVD. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 05, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at