chr2-201263895-A-C

Variant names:

• chr2-201263895-A-C
• rs6723097
• NM_001372051.1:c.-26-2566A>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.-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
• Publications: 20 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.-26-2566A>C		intron_variant	Intron 1 of 8	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.-26-2566A>C		intron_variant	Intron 1 of 8		NM_001372051.1	ENSP00000501268.1

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

African (AFR) AF: 0.195 AC: 8093 AN: 41548

American (AMR) AF: 0.448 AC: 6841 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1575 AN: 3468

East Asian (EAS) AF: 0.474 AC: 2456 AN: 5178

South Asian (SAS) AF: 0.350 AC: 1690 AN: 4822

European-Finnish (FIN) AF: 0.570 AC: 6017 AN: 10556

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42093 AN: 67970

Other (OTH) AF: 0.451 AC: 954 AN: 2114

Alfa AF: 0.563 Hom.: 10949

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
PhyloP100		0.040
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

Other links and lift over

dbSNP: rs6723097; hg19: chr2-202128618;