2-201279205-T-C

Variant names:

• chr2-201279205-T-C
• rs10931936
• NM_001372051.1:c.802+2237T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372051.1(CASP8):​c.802+2237T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 151,958 control chromosomes in the GnomAD database, including 39,494 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 0.72 (39494 hom., cov: 32)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 64 publications found

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]

CASP8 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372051.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	NM_001372051.1	MANE Select	c.802+2237T>C		intron	N/A	NP_001358980.1	Q14790-1
	CASP8	NM_001080125.2		c.979+2237T>C		intron	N/A	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.934+2237T>C		intron	N/A	NP_001387571.1	A0A8Q3SID9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000673742.1	MANE Select	c.802+2237T>C		intron	N/A	ENSP00000501268.1	Q14790-1
	CASP8	ENST00000358485.8	TSL:1	c.979+2237T>C		intron	N/A	ENSP00000351273.4	Q14790-9
	CASP8	ENST00000264275.9	TSL:1	c.853+2237T>C		intron	N/A	ENSP00000264275.5	Q14790-4

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109063 AN: 151842 Hom.: 39455 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.678

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

GnomAD4 genome AF: 0.718 AC: 109148 AN: 151958 Hom.: 39494 Cov.: 32 AF XY: 0.715 AC XY: 53117 AN XY: 74288

African (AFR) AF: 0.779 AC: 32215 AN: 41358

American (AMR) AF: 0.574 AC: 8758 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2167 AN: 3472

East Asian (EAS) AF: 0.698 AC: 3618 AN: 5186

South Asian (SAS) AF: 0.827 AC: 3991 AN: 4826

European-Finnish (FIN) AF: 0.665 AC: 7042 AN: 10584

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 49026 AN: 67972

Other (OTH) AF: 0.679 AC: 1427 AN: 2102

Alfa AF: 0.726 Hom.: 50201

Bravo AF: 0.710

Asia WGS AF: 0.794 AC: 2760 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.37
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10931936;

hg19: chr2-202143928;