4-76195788-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting
The NM_005506.4(SCARB2):c.194A>G(p.Tyr65Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0002 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005506.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCARB2 | NM_005506.4 | c.194A>G | p.Tyr65Cys | missense_variant | Exon 2 of 12 | ENST00000264896.8 | NP_005497.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000290 AC: 73AN: 251420Hom.: 0 AF XY: 0.000346 AC XY: 47AN XY: 135880
GnomAD4 exome AF: 0.000205 AC: 299AN: 1461522Hom.: 0 Cov.: 30 AF XY: 0.000264 AC XY: 192AN XY: 727098
GnomAD4 genome AF: 0.000158 AC: 24AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74448
ClinVar
Submissions by phenotype
Action myoclonus-renal failure syndrome Uncertain:3
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The missense c.194A>G p.Tyr65Cys variant in SCARB2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Tyr65Cys variant is present with allele frequency of 0.03% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance multiple submissions. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position in SCARB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Tyr at position 65 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. In absence of another reportable variant in SCARB2 gene, the molecular diagnosis is not confirmed. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Progressive myoclonic epilepsy Uncertain:1
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 65 of the SCARB2 protein (p.Tyr65Cys). This variant is present in population databases (rs138955932, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SCARB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 206708). 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 SCARB2 protein function with a positive predictive value of 80%. 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