rs17860422
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001372051.1(CASP8):c.339C>T(p.Ser113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,608,458 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0038 ( 26 hom. )
Consequence
CASP8
NM_001372051.1 synonymous
NM_001372051.1 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.689
Genes affected
CASP8 (HGNC:1509): (caspase 8) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
Variant 2-201271549-C-T is Benign according to our data. Variant chr2-201271549-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 333498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.689 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0031 (473/152356) while in subpopulation NFE AF= 0.00472 (321/68040). AF 95% confidence interval is 0.00429. There are 1 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 26 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASP8 | NM_001372051.1 | c.339C>T | p.Ser113= | synonymous_variant | 3/9 | ENST00000673742.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASP8 | ENST00000673742.1 | c.339C>T | p.Ser113= | synonymous_variant | 3/9 | NM_001372051.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00311 AC: 474AN: 152238Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00347 AC: 872AN: 251394Hom.: 4 AF XY: 0.00356 AC XY: 483AN XY: 135864
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GnomAD4 exome AF: 0.00379 AC: 5514AN: 1456102Hom.: 26 Cov.: 28 AF XY: 0.00380 AC XY: 2753AN XY: 724764
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GnomAD4 genome ? AF: 0.00310 AC: 473AN: 152356Hom.: 1 Cov.: 32 AF XY: 0.00321 AC XY: 239AN XY: 74504
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autoimmune lymphoproliferative syndrome type 2B Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Lung cancer;C0346153:Familial cancer of breast;C1846545:Autoimmune lymphoproliferative syndrome type 2B;C2239176:Hepatocellular carcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | CASP8: BP4, BP7, BS2 - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at