rs1045487

chr2-201284973-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001372051.1(CASP8):c.960G>A(p.Lys320=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,613,906 control chromosomes in the GnomAD database, including 7,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1334 hom., cov: 32)
  • Exomes 𝑓: 0.069 (6522 hom.)
• Consequence: CASP8 NM_001372051.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.321

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-201284973-G-A is Benign according to our data. Variant chr2-201284973-G-A is described in ClinVar as [Benign]. Clinvar id is 333505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.321 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001372051.1	c.960G>A	p.Lys320=	synonymous_variant	8/9	ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1	c.960G>A	p.Lys320=	synonymous_variant	8/9		NM_001372051.1	P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15765 AN: 151950 Hom.: 1326 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.0948 AC: 23830 AN: 251464 Hom.: 2045 AF XY: 0.101 AC XY: 13777 AN XY: 135908

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0840

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.0399

Gnomad NFE exome AF: 0.0490

Gnomad OTH exome AF: 0.0698

GnomAD4 exome AF: 0.0692 AC: 101220 AN: 1461836 Hom.: 6522 Cov.: 35 AF XY: 0.0747 AC XY: 54313 AN XY: 727220

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.0327

Gnomad4 ASJ exome AF: 0.0846

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.0409

Gnomad4 NFE exome AF: 0.0463

Gnomad4 OTH exome AF: 0.0827

GnomAD4 genome AF: 0.104 AC: 15805 AN: 152070 Hom.: 1334 Cov.: 32 AF XY: 0.107 AC XY: 7946 AN XY: 74336

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0493

Gnomad4 ASJ AF: 0.0818

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.0389

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0599 Hom.: 554

Bravo AF: 0.107

Asia WGS AF: 0.227 AC: 789 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	6.0
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1045487; hg19: chr2-202149696; COSMIC: COSV51848852; COSMIC: COSV51848852;