chr2-201263224-A-C

Position:

• chr2-201263224-A-C

Variant summary

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

The NM_001372051.1(CASP8):​c.-27+2611A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 152,044 control chromosomes in the GnomAD database, including 40,679 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 0.73 (40679 hom., cov: 32)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.287

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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.-27+2611A>C		intron_variant		ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.-27+2611A>C		intron_variant			NM_001372051.1	ENSP00000501268	P1

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110662 AN: 151926 Hom.: 40640 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.728 AC: 110748 AN: 152044 Hom.: 40679 Cov.: 32 AF XY: 0.725 AC XY: 53868 AN XY: 74332

Gnomad4 AFR AF: 0.777

Gnomad4 AMR AF: 0.580

Gnomad4 ASJ AF: 0.634

Gnomad4 EAS AF: 0.711

Gnomad4 SAS AF: 0.830

Gnomad4 FIN AF: 0.686

Gnomad4 NFE AF: 0.738

Gnomad4 OTH AF: 0.687

Alfa AF: 0.711 Hom.: 6514

Bravo AF: 0.719

Asia WGS AF: 0.799 AC: 2779 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.2
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: rs6435074; hg19: chr2-202127947;