rs6723097

chr2-201263895-A-Cchr2-201263895-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372051.1(CASP8):c.-26-2566A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 152,132 control chromosomes in the GnomAD database, including 18,811 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (18811 hom., cov: 33)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0400

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001372051.1	c.-26-2566A>C		intron_variant		ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1	c.-26-2566A>C		intron_variant			NM_001372051.1	P1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70398 AN: 152014 Hom.: 18819 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.453

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.463 AC: 70377 AN: 152132 Hom.: 18811 Cov.: 33 AF XY: 0.456 AC XY: 33929 AN XY: 74346

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.448

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.451

Alfa AF: 0.528 Hom.: 5386

Bravo AF: 0.446

Asia WGS AF: 0.395 AC: 1375 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	5.2
Dann	Benign	0.70

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: rs6723097; hg19: chr2-202128618;