rs200261147
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001372051.1(CASP8):c.159G>A(p.Met53Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Consequence
NM_001372051.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASP8 | NM_001372051.1 | c.159G>A | p.Met53Ile | missense_variant | 2/9 | ENST00000673742.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASP8 | ENST00000673742.1 | c.159G>A | p.Met53Ile | missense_variant | 2/9 | NM_001372051.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152178Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000147 AC: 37AN: 251366Hom.: 1 AF XY: 0.0000810 AC XY: 11AN XY: 135844
GnomAD4 exome AF: 0.0000369 AC: 54AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727242
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152178Hom.: 1 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74352
ClinVar
Submissions by phenotype
Autoimmune lymphoproliferative syndrome type 2B Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Nov 09, 2018 | CASP8 NM_001228.4 exon 3 p.Met53Ile (c.159G>A): This variant has not been reported in the literature and is present in 0.1% (36/34588) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-202131368-G-A), including 1 homozygote. This variant is present in ClinVar (Variation ID:533728). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 53 of the CASP8 protein (p.Met53Ile). This variant is present in population databases (rs200261147, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CASP8-related conditions. ClinVar contains an entry for this variant (Variation ID: 625904). 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 not expected to disrupt CASP8 protein function. 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. - |
Lung cancer;C0346153:Familial cancer of breast;C1846545:Autoimmune lymphoproliferative syndrome type 2B;C2239176:Hepatocellular carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | CASP8 NM_001228.4 exon 3 p.Met53Ile (c.159G>A): This variant has not been reported in the literature and is present in 0.1% (36/34588) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-202131368-G-A), including 1 homozygote. This variant is present in ClinVar (Variation ID:533728). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at