rs1035140

chr2-201287768-T-Achr2-201287768-T-G

Variant summary

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

The ENST00000696069.1(CASP8):c.1259+2451T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 152,030 control chromosomes in the GnomAD database, including 16,737 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 (16734 hom., cov: 32)
  • Exomes 𝑓: 0.75 (3 hom.)
• Consequence: CASP8 ENST00000696069.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43

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=-0.64).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000696069.1	c.1259+2451T>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69924 AN: 151900 Hom.: 16737 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.750 AC: 9 AN: 12 Hom.: 3 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad4 NFE exome AF: 0.750

GnomAD4 genome AF: 0.460 AC: 69921 AN: 152018 Hom.: 16734 Cov.: 32 AF XY: 0.458 AC XY: 34016 AN XY: 74306

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.416

Gnomad4 ASJ AF: 0.477

Gnomad4 EAS AF: 0.489

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.539

Gnomad4 OTH AF: 0.428

Alfa AF: 0.498 Hom.: 2303

Bravo AF: 0.448

Asia WGS AF: 0.438 AC: 1524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	12
Dann	Benign	0.86

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1035140; hg19: chr2-202152491;