2-201255044-T-C

Variant names:

• chr2-201255044-T-C
• rs13402616
• ENST00000264275.9:c.-26-11417T>C

Variant summary

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

The ENST00000264275.9(CASP8):​c.-26-11417T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,238 control chromosomes in the GnomAD database, including 3,192 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 0.15 (3192 hom., cov: 32)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.764
• Publications: 16 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001228.5	c.-26-11417T>C		intron_variant	Intron 2 of 9		NP_001219.2
CASP8	NM_001400648.1	c.-26-11417T>C		intron_variant	Intron 2 of 9		NP_001387577.1
CASP8	NM_001400651.1	c.-26-11417T>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.-26-11417T>C		intron_variant	Intron 2 of 9	1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-26-11417T>C		intron_variant	Intron 2 of 7	1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.251-11417T>C		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23498 AN: 152120 Hom.: 3171 Cov.: 32

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.0932

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0748

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0715

Gnomad OTH AF: 0.129

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

GnomAD4 genome AF: 0.155 AC: 23570 AN: 152238 Hom.: 3192 Cov.: 32 AF XY: 0.154 AC XY: 11467 AN XY: 74446

African (AFR) AF: 0.361 AC: 15002 AN: 41508

American (AMR) AF: 0.0800 AC: 1225 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0932 AC: 323 AN: 3466

East Asian (EAS) AF: 0.0121 AC: 63 AN: 5188

South Asian (SAS) AF: 0.198 AC: 953 AN: 4824

European-Finnish (FIN) AF: 0.0748 AC: 794 AN: 10608

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0715 AC: 4864 AN: 68018

Other (OTH) AF: 0.132 AC: 279 AN: 2114

Alfa AF: 0.0952 Hom.: 4199

Bravo AF: 0.159

Asia WGS AF: 0.155 AC: 541 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.59
DANN	Benign	0.56
PhyloP100		-0.76
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: rs13402616; hg19: chr2-202119767;