rs1045494

Positions:

chr2-201287058-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.37

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	UniProt
CASP8	NM_001372051.1 linkuse as main transcript	c.*464T>C		3_prime_UTR_variant	9/9	ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1 linkuse as main transcript	c.*464T>C		3_prime_UTR_variant	9/9		NM_001372051.1	P1	Q14790-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15836

AN:

152176

Hom.:

1339

Cov.:

show subpopulations

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.:

AF XY:

0.108

AC XY:

2053

AN XY:

19088

show subpopulations

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.:

AF XY:

0.107

AC XY:

7996

AN XY:

74470

show subpopulations

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

LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over