2-201246297-C-A

Variant names:

• chr2-201246297-C-A
• rs3820972
• ENST00000264275.9:c.-27+12185C>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+12185C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.877 in 152,188 control chromosomes in the GnomAD database, including 58,808 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 0.88 (58808 hom., cov: 30)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 5 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 (NFE) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001228.5	c.-27+12185C>A		intron_variant	Intron 2 of 9		NP_001219.2
CASP8	NM_001400648.1	c.-27+12185C>A		intron_variant	Intron 2 of 9		NP_001387577.1
CASP8	NM_001400651.1	c.-27+12185C>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+12185C>A		intron_variant	Intron 2 of 9	1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-27+12185C>A		intron_variant	Intron 2 of 7	1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.250+12185C>A		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.877 AC: 133367 AN: 152070 Hom.: 58763 Cov.: 30

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.927

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.968

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.873

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

GnomAD4 genome AF: 0.877 AC: 133467 AN: 152188 Hom.: 58808 Cov.: 30 AF XY: 0.874 AC XY: 65041 AN XY: 74416

African (AFR) AF: 0.835 AC: 34641 AN: 41478

American (AMR) AF: 0.865 AC: 13224 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.927 AC: 3219 AN: 3472

East Asian (EAS) AF: 0.773 AC: 3990 AN: 5164

South Asian (SAS) AF: 0.684 AC: 3301 AN: 4826

European-Finnish (FIN) AF: 0.968 AC: 10274 AN: 10614

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.911 AC: 61998 AN: 68030

Other (OTH) AF: 0.873 AC: 1841 AN: 2110

Alfa AF: 0.899 Hom.: 34609

Bravo AF: 0.869

Asia WGS AF: 0.718 AC: 2501 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	0.41
DANN	Benign	0.53
PhyloP100		-1.4
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: rs3820972; hg19: chr2-202111020;