rs201864483
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6
The NM_000492.4(CFTR):c.2684G>A(p.Ser895Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. S895G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2684G>A | p.Ser895Asn | missense_variant | 17/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2684G>A | p.Ser895Asn | missense_variant | 17/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000350 AC: 88AN: 251266Hom.: 0 AF XY: 0.000361 AC XY: 49AN XY: 135794
GnomAD4 exome AF: 0.0000712 AC: 104AN: 1461632Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50AN XY: 727104
GnomAD4 genome ? AF: 0.0000919 AC: 14AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74486
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2017 | - - |
CFTR-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 30, 2023 | The CFTR c.2684G>A variant is predicted to result in the amino acid substitution p.Ser895Asn. This variant has been reported in patients with pancreatitis (Table 3, Palermo et al. 2016. PubMed ID: 27171515; Chang et al. 2007. PubMed ID: 17539902; Chang et al. 2015. PubMed ID: 25869325) and bronchiectasis (Guan et al. 2018. PubMed ID: 29997923). The patient discussed in Guan et al. was also homozygous for a different variant in CFTR. This variant is reported in 0.46% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117243612-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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. - |
not specified Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 20, 2022 | Variant summary: CFTR c.2684G>A (p.Ser895Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251266 control chromosomes, predominantly at a frequency of 0.0048 within the East Asian subpopulation in the gnomAD database. The variant occurs with an even higher frequency in the Other East-Asian (presumably mostly Chinese) sub population (i.e. with a frequency of 0.006), and although this frequency is not higher than the estimated maximum expected for a pathogenic variant in CFTR causing Cystic Fibrosis (CF) in the Caucasian population (0.013), however, in a recent study the estimated Chinese CF prevalence was reported to be about 40x lower than the prevalence in Caucasians (Ni_2022), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.2684G>A, has been reported in the literature in four Chinese individuals affected with Cystic Fibrosis (Wu_2000, Alper_2003, Wang_2019, Yang_2021), however, in all of these patients the variant occurred in cis with a pathogenic variant (c.2083dupG (p.Glu695fs)), and all patients also carried a pathogenic variant (c.1898+5G>T) in trans, therefore these co-occurrences with other pathogenic variants provide supporting evidence for a benign role. The variant was also reported in two Chinese patients affected with congenital absence of vas deferens (CAVD; Luo_2021), however one of these patients also carried the variant c.2083dupG (p.Glu695fs) which was described earlier in cis in four Chinese CF patients, while the other patient carried two (potentially) pathogenic variants which could explain the phenotype (though the phase was not specified). In addition, the variant was published in heterozygous state in individuals affected with pancreatitis (Chang_2015, Palermo_2016) and bronchiectasis (Guan_2018), but was also found in healthy subject with a similar frequency (Guan_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 09, 2017 | - - |
Hereditary pancreatitis Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 24, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 09, 2020 | - - |
Breast neoplasm Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ACT Genomics, | Nov 06, 2020 | The allele frequency of this variant c.2684G>A (p.Ser895Asn) is 0.0026 in East Asian of gnomAD and 0.003 in East Asian in 1000 Genomes. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at