8-31116451-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000553.6(WRN):c.2371T>G(p.Cys791Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,613,936 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 Uncertain significance (★★).
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.2371T>G | p.Cys791Gly | missense_variant | Exon 20 of 35 | 1 | NM_000553.6 | ENSP00000298139.5 | ||
WRN | ENST00000521620.5 | n.1004T>G | non_coding_transcript_exon_variant | Exon 8 of 23 | 1 | |||||
WRN | ENST00000650667.1 | n.*1985T>G | non_coding_transcript_exon_variant | Exon 19 of 34 | ENSP00000498593.1 | |||||
WRN | ENST00000650667.1 | n.*1985T>G | 3_prime_UTR_variant | Exon 19 of 34 | ENSP00000498593.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251260Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135802
GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461744Hom.: 0 Cov.: 33 AF XY: 0.0000536 AC XY: 39AN XY: 727172
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
not specified Uncertain:1
DNA sequence analysis of the WRN gene demonstrated a sequence change, c.2371T>G, in exon 20 that results in an amino acid change, p.Cys791Gly. This sequence change has been described in the gnomAD database with a frequency of 0.011% in the non-Finnish European subpopulation (dbSNP rs200169079). The p.Cys791Gly change affects a highly conserved amino acid residue located in a domain of the WRN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys791Gly substitution. This sequence change does not appear to have been previously described in individuals with WRN-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Cys791Gly change remains unknown at this time. -
Werner syndrome Uncertain:1
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 791 of the WRN protein (p.Cys791Gly). This variant is present in population databases (rs200169079, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 528106). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at