chr2-201287058-T-C

Position:

• chr2-201287058-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001372051.1(CASP8):​c.*464T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 188,986 control chromosomes in the GnomAD database, including 1,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1347 hom., cov: 32)
  • Exomes 𝑓: 0.094 (315 hom.)
• Consequence: CASP8 NM_001372051.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.37

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-201287058-T-C is Benign according to our data. Variant chr2-201287058-T-C is described in ClinVar as [Benign]. Clinvar id is 333520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.*464T>C		3_prime_UTR_variant	9/9	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.*464T>C		3_prime_UTR_variant	9/9		NM_001372051.1	ENSP00000501268	P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15836 AN: 152176 Hom.: 1339 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.0936 AC: 3433 AN: 36692 Hom.: 315 Cov.: 0 AF XY: 0.108 AC XY: 2053 AN XY: 19088

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.0307

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.252

Gnomad4 FIN exome AF: 0.0423

Gnomad4 NFE exome AF: 0.0450

Gnomad4 OTH exome AF: 0.0845

GnomAD4 genome AF: 0.104 AC: 15876 AN: 152294 Hom.: 1347 Cov.: 32 AF XY: 0.107 AC XY: 7996 AN XY: 74470

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.0492

Gnomad4 ASJ AF: 0.0819

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.0389

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0569 Hom.: 439

Bravo AF: 0.107

Asia WGS AF: 0.230 AC: 798 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.3
DANN	Benign	0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1045494; hg19: chr2-202151781; COSMIC: COSV104376363; COSMIC: COSV104376363;