2-201266864-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001372051.1(CASP8):c.305+73T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,141,694 control chromosomes in the GnomAD database, including 16,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (4302 hom., cov: 31)
  • Exomes 𝑓: 0.12 (12042 hom.)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.299

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-201266864-T-G is Benign according to our data. Variant chr2-201266864-T-G is described in ClinVar as [Benign]. Clinvar id is 1292384.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001372051.1	c.305+73T>G		intron_variant		ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1	c.305+73T>G		intron_variant			NM_001372051.1	P1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27958 AN: 151872 Hom.: 4275 Cov.: 31

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.0784

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.0751

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.116 AC: 114603 AN: 989704 Hom.: 12042 AF XY: 0.125 AC XY: 62598 AN XY: 499018

Gnomad4 AFR exome AF: 0.415

Gnomad4 AMR exome AF: 0.0627

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.235

Gnomad4 SAS exome AF: 0.423

Gnomad4 FIN exome AF: 0.0847

Gnomad4 NFE exome AF: 0.0759

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.185 AC: 28044 AN: 151990 Hom.: 4302 Cov.: 31 AF XY: 0.188 AC XY: 13964 AN XY: 74324

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.0870

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.0784

Gnomad4 NFE AF: 0.0752

Gnomad4 OTH AF: 0.164

Alfa AF: 0.0973 Hom.: 2210

Bravo AF: 0.189

Asia WGS AF: 0.355 AC: 1236 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	1.1
Dann	Benign	0.59

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: rs2293554; hg19: chr2-202131587; COSMIC: COSV51849443;