chr2-201254251-G-C

Variant names:

• chr2-201254251-G-C
• rs6736233
• ENST00000264275.9:c.-26-12210G>C

Variant summary

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

The ENST00000264275.9(CASP8):​c.-26-12210G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,116 control chromosomes in the GnomAD database, including 3,507 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 0.16 (3507 hom., cov: 32)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.192
• Publications: 7 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001228.5	c.-26-12210G>C		intron_variant	Intron 2 of 9		NP_001219.2
CASP8	NM_001400648.1	c.-26-12210G>C		intron_variant	Intron 2 of 9		NP_001387577.1
CASP8	NM_001400651.1	c.-26-12210G>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.-26-12210G>C		intron_variant	Intron 2 of 9	1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-26-12210G>C		intron_variant	Intron 2 of 7	1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.251-12210G>C		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24347 AN: 151998 Hom.: 3488 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0813

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0717

Gnomad OTH AF: 0.135

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

GnomAD4 genome AF: 0.161 AC: 24418 AN: 152116 Hom.: 3507 Cov.: 32 AF XY: 0.160 AC XY: 11883 AN XY: 74372

African (AFR) AF: 0.382 AC: 15807 AN: 41432

American (AMR) AF: 0.0812 AC: 1242 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 326 AN: 3472

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5184

South Asian (SAS) AF: 0.198 AC: 952 AN: 4818

European-Finnish (FIN) AF: 0.0750 AC: 795 AN: 10606

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0717 AC: 4874 AN: 67998

Other (OTH) AF: 0.138 AC: 292 AN: 2110

Alfa AF: 0.134 Hom.: 309

Bravo AF: 0.166

Asia WGS AF: 0.156 AC: 542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.50
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: rs6736233; hg19: chr2-202118974;