2-201258707-C-T

Position:

• chr2-201258707-C-T

Variant summary

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

The ENST00000358485.8(CASP8):​c.151+325C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 151,986 control chromosomes in the GnomAD database, including 26,078 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 0.57 (26078 hom., cov: 31)
• Consequence: CASP8 ENST00000358485.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.710

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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001080124.2	c.-26-7754C>T		intron_variant
CASP8	NM_001080125.2	c.151+325C>T		intron_variant
CASP8	NM_001228.4	c.-26-7754C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000264275.9	c.-26-7754C>T		intron_variant		1
CASP8	ENST00000358485.8	c.151+325C>T		intron_variant		1
CASP8	ENST00000392258.7	c.-26-7754C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87209 AN: 151868 Hom.: 26080 Cov.: 31

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.558

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

GnomAD4 genome AF: 0.574 AC: 87224 AN: 151986 Hom.: 26078 Cov.: 31 AF XY: 0.571 AC XY: 42411 AN XY: 74278

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.540

Gnomad4 EAS AF: 0.698

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.611

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.555

Alfa AF: 0.621 Hom.: 7647

Bravo AF: 0.560

Asia WGS AF: 0.641 AC: 2229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.63
DANN	Benign	0.88

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: rs3769821; hg19: chr2-202123430;