rs13113

chr2-201287439-T-Achr2-201287439-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001372051.1(CASP8):c.*845T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 154,542 control chromosomes in the GnomAD database, including 10,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (10138 hom., cov: 32)
  • Exomes 𝑓: 0.34 (166 hom.)
• Consequence: CASP8 NM_001372051.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.71

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-201287439-T-A is Benign according to our data. Variant chr2-201287439-T-A is described in ClinVar as [Benign]. Clinvar id is 333525.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001372051.1	c.*845T>A		3_prime_UTR_variant	9/9	ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1	c.*845T>A		3_prime_UTR_variant	9/9		NM_001372051.1	P1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50996 AN: 151888 Hom.: 10142 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.319

GnomAD4 exome AF: 0.340 AC: 863 AN: 2536 Hom.: 166 Cov.: 0 AF XY: 0.346 AC XY: 450 AN XY: 1302

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.250

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.485

Gnomad4 NFE exome AF: 0.483

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome AF: 0.335 AC: 50980 AN: 152006 Hom.: 10138 Cov.: 32 AF XY: 0.337 AC XY: 25005 AN XY: 74290

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.368

Gnomad4 EAS AF: 0.481

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.440

Gnomad4 OTH AF: 0.318

Alfa AF: 0.376 Hom.: 1447

Bravo AF: 0.318

Asia WGS AF: 0.380 AC: 1321 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.23
Dann	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs13113; hg19: chr2-202152162;