rs149933993
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting
The NM_001372051.1(CASP8):c.432A>G(p.Ile144Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,614,154 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I144T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001372051.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASP8 | NM_001372051.1 | c.432A>G | p.Ile144Met | missense_variant | 4/9 | ENST00000673742.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASP8 | ENST00000673742.1 | c.432A>G | p.Ile144Met | missense_variant | 4/9 | NM_001372051.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000274 AC: 69AN: 251382Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135868
GnomAD4 exome AF: 0.000322 AC: 471AN: 1461850Hom.: 3 Cov.: 33 AF XY: 0.000312 AC XY: 227AN XY: 727230
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74480
ClinVar
Submissions by phenotype
Autoimmune lymphoproliferative syndrome type 2B Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 176 of the CASP8 protein (p.Ile176Met). This variant is present in population databases (rs149933993, gnomAD 0.2%). 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: 333499). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 16, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | CASP8: PM2, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 16, 2019 | - - |
CASP8-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 21, 2022 | The CASP8 c.528A>G variant is predicted to result in the amino acid substitution p.Ile176Met. This variant has been reported in a patient with primary immunodeficiency (described as p.Ile203Met, Table S2, Kelsen et al. 2015. PubMed ID: 26193622). This variant is reported in 0.17% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-202137381-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at