2-201237962-A-G

Variant names:

• chr2-201237962-A-G
• rs3769827
• ENST00000264275.9:c.-27+3850A>G

Variant summary

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

The ENST00000264275.9(CASP8):​c.-27+3850A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 152,052 control chromosomes in the GnomAD database, including 13,381 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 0.41 (13381 hom., cov: 32)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.422
• 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 = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001228.5	c.-27+3850A>G		intron_variant	Intron 2 of 9		NP_001219.2
CASP8	NM_001400648.1	c.-27+3850A>G		intron_variant	Intron 2 of 9		NP_001387577.1
CASP8	NM_001400651.1	c.-27+3850A>G		intron_variant	Intron 2 of 9		NP_001387580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000264275.9	c.-27+3850A>G		intron_variant	Intron 2 of 9	1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-27+3850A>G		intron_variant	Intron 2 of 7	1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.250+3850A>G		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62508 AN: 151936 Hom.: 13382 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.429

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

GnomAD4 genome AF: 0.411 AC: 62511 AN: 152052 Hom.: 13381 Cov.: 32 AF XY: 0.404 AC XY: 30056 AN XY: 74322

African (AFR) AF: 0.333 AC: 13819 AN: 41468

American (AMR) AF: 0.384 AC: 5861 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1347 AN: 3470

East Asian (EAS) AF: 0.229 AC: 1185 AN: 5180

South Asian (SAS) AF: 0.242 AC: 1167 AN: 4828

European-Finnish (FIN) AF: 0.465 AC: 4910 AN: 10548

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32845 AN: 67976

Other (OTH) AF: 0.429 AC: 905 AN: 2110

Alfa AF: 0.452 Hom.: 45128

Bravo AF: 0.405

Asia WGS AF: 0.224 AC: 781 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	1.2
DANN	Benign	0.42
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3769827; hg19: chr2-202102685;