2-201258233-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PVS1_SupportingBP6_Very_StrongBA1

The NM_001080125.2(CASP8):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,607,054 control chromosomes in the GnomAD database, including 2,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 182 hom., cov: 31)

Exomes 𝑓: 0.045 ( 1854 hom. )

Consequence

CASP8
NM_001080125.2 start_lost

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.196

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 -15 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 43 codons. Genomic position: 201258358. Lost 0.079 part of the original CDS.

BP6

Variant 2-201258233-T-C is Benign according to our data. Variant chr2-201258233-T-C is described in ClinVar as [Benign]. Clinvar id is 402493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201258233-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
CASP8	NM_001080125.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	NP_001073594.1	Q14790-9
CASP8	NM_001400642.1 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	NP_001387571.1
CASP8	NM_001400665.1 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 6	NP_001387594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
CASP8	ENST00000358485.8 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	1	ENSP00000351273.4	Q14790-9
CASP8	ENST00000264275.9 link	c.-26-8228T>C		intron_variant	Intron 2 of 9	1	ENSP00000264275.5	Q14790-4
CASP8	ENST00000392258.7 link	c.-26-8228T>C		intron_variant	Intron 2 of 7	1	ENSP00000376087.3	Q14790-5

Frequencies

GnomAD3 genomes

AF:

0.0368

AC:

5565

AN:

151150

Hom.:

182

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00867

Gnomad AMI

AF:

0.0166

Gnomad AMR

AF:

0.0693

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0388

Gnomad FIN

AF:

0.0781

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0443

Gnomad OTH

AF:

0.0322

GnomAD3 exomes

AF:

0.0490

AC:

12206

AN:

249222

Hom.:

489

AF XY:

0.0464

AC XY:

6270

AN XY:

135188

show subpopulations

Gnomad AFR exome

AF:

0.00698

Gnomad AMR exome

AF:

0.120

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.00167

Gnomad SAS exome

AF:

0.0425

Gnomad FIN exome

AF:

0.0742

Gnomad NFE exome

AF:

0.0409

Gnomad OTH exome

AF:

0.0429

GnomAD4 exome

AF:

0.0452

AC:

65840

AN:

1455786

Hom.:

1854

Cov.:

AF XY:

0.0445

AC XY:

32240

AN XY:

724272

show subpopulations

Gnomad4 AFR exome

AF:

0.00652

Gnomad4 AMR exome

AF:

0.117

Gnomad4 ASJ exome

AF:

0.0136

Gnomad4 EAS exome

AF:

0.00383

Gnomad4 SAS exome

AF:

0.0427

Gnomad4 FIN exome

AF:

0.0701

Gnomad4 NFE exome

AF:

0.0451

Gnomad4 OTH exome

AF:

0.0410

GnomAD4 genome

AF:

0.0368

AC:

5567

AN:

151268

Hom.:

182

Cov.:

AF XY:

0.0381

AC XY:

2815

AN XY:

73942

show subpopulations

Gnomad4 AFR

AF:

0.00864

Gnomad4 AMR

AF:

0.0692

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0390

Gnomad4 FIN

AF:

0.0781

Gnomad4 NFE

AF:

0.0444

Gnomad4 OTH

AF:

0.0319

Alfa

AF:

0.0362

Hom.:

208

Bravo

AF:

0.0350

TwinsUK

AF:

0.0440

AC:

163

ALSPAC

AF:

0.0439

AC:

169

ESP6500AA

AF:

0.00898

AC:

ESP6500EA

AF:

0.0437

AC:

361

ExAC

AF:

0.0453

AC:

5479

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0393

EpiControl

AF:

0.0388

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 395/12046= 3.27% -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.61

CADD

Benign

3.5

DANN

Benign

0.68

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00090

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.91

PROVEAN

Benign

-0.090

REVEL

Benign

0.083

Sift

Pathogenic

0.0

Polyphen

0.0

Vest4

0.028

ClinPred

0.019

GERP RS

0.58

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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