rs2037815

Variant names:

• chr2-201236992-G-A
• rs2037815
• ENST00000264275.9:c.-27+2880G>A

Variant summary

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

The ENST00000264275.9(CASP8):​c.-27+2880G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,802 control chromosomes in the GnomAD database, including 23,175 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 0.54 (23175 hom., cov: 32)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650
• Publications: 21 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001228.5	c.-27+2880G>A		intron_variant	Intron 2 of 9		NP_001219.2
CASP8	NM_001400648.1	c.-27+2880G>A		intron_variant	Intron 2 of 9		NP_001387577.1
CASP8	NM_001400651.1	c.-27+2880G>A		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+2880G>A		intron_variant	Intron 2 of 9	1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-27+2880G>A		intron_variant	Intron 2 of 7	1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.250+2880G>A		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82045 AN: 151684 Hom.: 23133 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.523

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

GnomAD4 genome AF: 0.541 AC: 82140 AN: 151802 Hom.: 23175 Cov.: 32 AF XY: 0.531 AC XY: 39426 AN XY: 74182

African (AFR) AF: 0.691 AC: 28594 AN: 41376

American (AMR) AF: 0.444 AC: 6776 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1665 AN: 3472

East Asian (EAS) AF: 0.234 AC: 1210 AN: 5170

South Asian (SAS) AF: 0.307 AC: 1477 AN: 4818

European-Finnish (FIN) AF: 0.502 AC: 5263 AN: 10488

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.523 AC: 35536 AN: 67914

Other (OTH) AF: 0.529 AC: 1113 AN: 2104

Alfa AF: 0.526 Hom.: 10542

Bravo AF: 0.543

Asia WGS AF: 0.299 AC: 1042 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.0
DANN	Benign	0.58
PhyloP100		0.065
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: rs2037815; hg19: chr2-202101715;