2-201250111-C-T

Variant names:

• chr2-201250111-C-T
• rs7570325
• ENST00000264275.9:c.-27+15999C>T

Variant summary

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

The ENST00000264275.9(CASP8):​c.-27+15999C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0913 in 152,056 control chromosomes in the GnomAD database, including 1,204 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 0.091 (1204 hom., cov: 32)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.19
• Publications: 2 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001228.5	c.-27+15999C>T		intron_variant	Intron 2 of 9		NP_001219.2
CASP8	NM_001400648.1	c.-27+15999C>T		intron_variant	Intron 2 of 9		NP_001387577.1
CASP8	NM_001400651.1	c.-27+15999C>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+15999C>T		intron_variant	Intron 2 of 9	1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-27+15999C>T		intron_variant	Intron 2 of 7	1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.250+15999C>T		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.0912 AC: 13856 AN: 151938 Hom.: 1201 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0450

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.0861

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

GnomAD4 genome AF: 0.0913 AC: 13878 AN: 152056 Hom.: 1204 Cov.: 32 AF XY: 0.0919 AC XY: 6829 AN XY: 74348

African (AFR) AF: 0.225 AC: 9309 AN: 41400

American (AMR) AF: 0.0450 AC: 688 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3472

East Asian (EAS) AF: 0.00599 AC: 31 AN: 5174

South Asian (SAS) AF: 0.149 AC: 717 AN: 4814

European-Finnish (FIN) AF: 0.0420 AC: 445 AN: 10592

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0341 AC: 2316 AN: 68006

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0481 Hom.: 312

Bravo AF: 0.0954

Asia WGS AF: 0.115 AC: 402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.66
PhyloP100		-2.2
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: rs7570325; hg19: chr2-202114834;