2-201284866-G-C

Position:

chr2-201284866-G-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.853G>C(p.Asp285His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,940 control chromosomes in the GnomAD database, including 12,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D285N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.098 ( 826 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11184 hom. )

Consequence

CASP8
NM_001372051.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.867

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 (MetaRNN=0.0031588674).

BP6

Variant 2-201284866-G-C is Benign according to our data. Variant chr2-201284866-G-C is described in ClinVar as [Benign]. Clinvar id is 7762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201284866-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 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.853G>C	p.Asp285His	missense_variant	8/9	ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1 linkuse as main transcript	c.853G>C	p.Asp285His	missense_variant	8/9		NM_001372051.1	P1	Q14790-1

Frequencies

GnomAD3 genomes

AF:

0.0981

AC:

14907

AN:

152028

Hom.:

821

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0670

Gnomad AMI

AF:

0.272

Gnomad AMR

AF:

0.0866

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0381

Gnomad FIN

AF:

0.0981

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.108

GnomAD3 exomes

AF:

0.0898

AC:

22585

AN:

251456

Hom.:

1302

AF XY:

0.0893

AC XY:

12136

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0654

Gnomad AMR exome

AF:

0.0574

Gnomad ASJ exome

AF:

0.0592

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0438

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.117

AC:

171410

AN:

1461794

Hom.:

11184

Cov.:

AF XY:

0.115

AC XY:

83814

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0631

Gnomad4 AMR exome

AF:

0.0605

Gnomad4 ASJ exome

AF:

0.0628

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0467

Gnomad4 FIN exome

AF:

0.106

Gnomad4 NFE exome

AF:

0.133

Gnomad4 OTH exome

AF:

0.110

GnomAD4 genome

AF:

0.0982

AC:

14942

AN:

152146

Hom.:

826

Cov.:

AF XY:

0.0947

AC XY:

7048

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0678

Gnomad4 AMR

AF:

0.0864

Gnomad4 ASJ

AF:

0.0622

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0386

Gnomad4 FIN

AF:

0.0981

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.107

Alfa

AF:

0.0983

Hom.:

297

Bravo

AF:

0.0961

TwinsUK

AF:

0.138

AC:

512

ALSPAC

AF:

0.133

AC:

514

ESP6500AA

AF:

0.0717

AC:

316

ESP6500EA

AF:

0.129

AC:

1111

ExAC

AF:

0.0907

AC:

11008

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

EpiCase

AF:

0.130

EpiControl

AF:

0.125

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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:1Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 19843670, 19214744, 19203830, 19318553, 20176653, 16251207, 18398042, 20978178, 20502973, 17293864, 25502557, 20033885, 15601643, 28674227, 22588838) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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: MAF -

Breast cancer, protection against

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Mar 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.58

DANN

Benign

0.41

DEOGEN2

Benign

0.11

.;T;.;.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.15

T;T;T;T;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

.;L;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.88

N;N;N;N;N;N

REVEL

Benign

0.0

Sift

Benign

0.099

T;T;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.13

B;B;B;B;B;.

Vest4

0.054

MPC

0.35

ClinPred

0.0036

GERP RS

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.44

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