rs3769826

Variant names:

• chr2-201238326-A-C
• rs3769826
• ENST00000264275.9:c.-27+4214A>C

Variant summary

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

The ENST00000264275.9(CASP8):​c.-27+4214A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 152,048 control chromosomes in the GnomAD database, including 21,090 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 0.52 (21090 hom., cov: 32)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.193
• Publications: 8 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) 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_001228.5	c.-27+4214A>C		intron_variant	Intron 2 of 9		NP_001219.2
CASP8	NM_001400648.1	c.-27+4214A>C		intron_variant	Intron 2 of 9		NP_001387577.1
CASP8	NM_001400651.1	c.-27+4214A>C		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+4214A>C		intron_variant	Intron 2 of 9	1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-27+4214A>C		intron_variant	Intron 2 of 7	1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.250+4214A>C		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78867 AN: 151930 Hom.: 21075 Cov.: 32

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.511

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

GnomAD4 genome AF: 0.519 AC: 78917 AN: 152048 Hom.: 21090 Cov.: 32 AF XY: 0.509 AC XY: 37846 AN XY: 74336

African (AFR) AF: 0.620 AC: 25716 AN: 41462

American (AMR) AF: 0.431 AC: 6588 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1608 AN: 3470

East Asian (EAS) AF: 0.234 AC: 1210 AN: 5176

South Asian (SAS) AF: 0.301 AC: 1452 AN: 4822

European-Finnish (FIN) AF: 0.499 AC: 5271 AN: 10568

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35479 AN: 67962

Other (OTH) AF: 0.517 AC: 1088 AN: 2106

Alfa AF: 0.517 Hom.: 14292

Bravo AF: 0.521

Asia WGS AF: 0.281 AC: 979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.86
DANN	Benign	0.41
PhyloP100		-0.19
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: rs3769826; hg19: chr2-202103049;