2-201246297-C-T

Variant names:

• chr2-201246297-C-T
• rs3820972
• ENST00000264275.9:c.-27+12185C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The ENST00000264275.9(CASP8):​c.-27+12185C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00012 (0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000118 (18/152220) while in subpopulation AFR AF = 0.000361 (15/41496). AF 95% confidence interval is 0.000222. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152102 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152220 Hom.: 0 Cov.: 30 AF XY: 0.0000806 AC XY: 6 AN XY: 74436

African (AFR) AF: 0.000361 AC: 15 AN: 41496

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 34609

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.58
DANN	Benign	0.84
PhyloP100		-1.4

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;