2-201266864-T-G

Variant names:

• chr2-201266864-T-G
• rs2293554
• NM_001372051.1:c.305+73T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001372051.1(CASP8):​c.305+73T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,141,694 control chromosomes in the GnomAD database, including 16,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4302 hom., cov: 31)
  • Exomes 𝑓: 0.12 (12042 hom.)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.299
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-201266864-T-G is Benign according to our data. Variant chr2-201266864-T-G is described in ClinVar as Benign. ClinVar VariationId is 1292384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.305+73T>G		intron_variant	Intron 2 of 8	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.305+73T>G		intron_variant	Intron 2 of 8		NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27958 AN: 151872 Hom.: 4275 Cov.: 31

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.0784

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.0751

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.116 AC: 114603 AN: 989704 Hom.: 12042 AF XY: 0.125 AC XY: 62598 AN XY: 499018

African (AFR) AF: 0.415 AC: 9694 AN: 23362

American (AMR) AF: 0.0627 AC: 1668 AN: 26616

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 2436 AN: 18464

East Asian (EAS) AF: 0.235 AC: 8466 AN: 36086

South Asian (SAS) AF: 0.423 AC: 26471 AN: 62626

European-Finnish (FIN) AF: 0.0847 AC: 3711 AN: 43792

Middle Eastern (MID) AF: 0.195 AC: 815 AN: 4184

European-Non Finnish (NFE) AF: 0.0759 AC: 55422 AN: 730526

Other (OTH) AF: 0.134 AC: 5920 AN: 44048

GnomAD4 genome AF: 0.185 AC: 28044 AN: 151990 Hom.: 4302 Cov.: 31 AF XY: 0.188 AC XY: 13964 AN XY: 74324

African (AFR) AF: 0.400 AC: 16576 AN: 41402

American (AMR) AF: 0.0870 AC: 1330 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3468

East Asian (EAS) AF: 0.216 AC: 1116 AN: 5174

South Asian (SAS) AF: 0.428 AC: 2059 AN: 4806

European-Finnish (FIN) AF: 0.0784 AC: 829 AN: 10578

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.0752 AC: 5109 AN: 67968

Other (OTH) AF: 0.164 AC: 347 AN: 2110

Alfa AF: 0.113 Hom.: 6953

Bravo AF: 0.189

Asia WGS AF: 0.355 AC: 1236 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2293554; hg19: chr2-202131587; COSMIC: COSV51849443;