2-201258272-A-G

Position:

chr2-201258272-A-G

Variant summary

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

The ENST00000358485.8(CASP8):c.41A>G(p.Lys14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,612,910 control chromosomes in the GnomAD database, including 387,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32194 hom., cov: 29)

Exomes 𝑓: 0.70 ( 355271 hom. )

Consequence

CASP8
ENST00000358485.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.73

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:

CASP8 (HGNC:):

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=2.249959E-6).

BP6

Variant 2-201258272-A-G is Benign according to our data. Variant chr2-201258272-A-G is described in ClinVar as [Benign]. Clinvar id is 402492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
CASP8	NM_001080125.2 linkuse as main transcript	c.41A>G	p.Lys14Arg	missense_variant	1/9	NP_001073594.1	Q14790-9
CASP8	NM_001400642.1 linkuse as main transcript	c.41A>G	p.Lys14Arg	missense_variant	1/8	NP_001387571.1
CASP8	NM_001400665.1 linkuse as main transcript	c.41A>G	p.Lys14Arg	missense_variant	1/6	NP_001387594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
CASP8	ENST00000358485.8 linkuse as main transcript	c.41A>G	p.Lys14Arg	missense_variant	1/9	1	ENSP00000351273.4	Q14790-9
CASP8	ENST00000264275.9 linkuse as main transcript	c.-26-8189A>G		intron_variant		1	ENSP00000264275.5	Q14790-4
CASP8	ENST00000392258.7 linkuse as main transcript	c.-26-8189A>G		intron_variant		1	ENSP00000376087.3	Q14790-5

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98187

AN:

151618

Hom.:

32170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.577

Gnomad AMI

AF:

0.749

Gnomad AMR

AF:

0.565

Gnomad ASJ

AF:

0.585

Gnomad EAS

AF:

0.708

Gnomad SAS

AF:

0.680

Gnomad FIN

AF:

0.646

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.705

Gnomad OTH

AF:

0.610

GnomAD3 exomes

AF:

0.660

AC:

164673

AN:

249496

Hom.:

54987

AF XY:

0.666

AC XY:

90116

AN XY:

135366

show subpopulations

Gnomad AFR exome

AF:

0.576

Gnomad AMR exome

AF:

0.539

Gnomad ASJ exome

AF:

0.577

Gnomad EAS exome

AF:

0.710

Gnomad SAS exome

AF:

0.680

Gnomad FIN exome

AF:

0.648

Gnomad NFE exome

AF:

0.706

Gnomad OTH exome

AF:

0.647

GnomAD4 exome

AF:

0.696

AC:

1016284

AN:

1461174

Hom.:

355271

Cov.:

AF XY:

0.695

AC XY:

505524

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.565

Gnomad4 AMR exome

AF:

0.544

Gnomad4 ASJ exome

AF:

0.584

Gnomad4 EAS exome

AF:

0.699

Gnomad4 SAS exome

AF:

0.676

Gnomad4 FIN exome

AF:

0.650

Gnomad4 NFE exome

AF:

0.713

Gnomad4 OTH exome

AF:

0.674

GnomAD4 genome

AF:

0.648

AC:

98265

AN:

151736

Hom.:

32194

Cov.:

AF XY:

0.644

AC XY:

47710

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.577

Gnomad4 AMR

AF:

0.564

Gnomad4 ASJ

AF:

0.585

Gnomad4 EAS

AF:

0.707

Gnomad4 SAS

AF:

0.682

Gnomad4 FIN

AF:

0.646

Gnomad4 NFE

AF:

0.705

Gnomad4 OTH

AF:

0.612

Alfa

AF:

0.690

Hom.:

91334

Bravo

AF:

0.637

TwinsUK

AF:

0.723

AC:

2680

ALSPAC

AF:

0.724

AC:

2791

ESP6500AA

AF:

0.592

AC:

2286

ESP6500EA

AF:

0.706

AC:

5832

ExAC

AF:

0.667

AC:

80598

Asia WGS

AF:

0.684

AC:

2380

AN:

3478

EpiCase

AF:

0.692

EpiControl

AF:

0.702

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 80% of patients studied by a panel of primary immunodeficiencies. Number of patients: 77. Only high quality variants are reported. -
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: Frequency -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2018	This variant is associated with the following publications: (PMID: 29083408) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autoimmune lymphoproliferative syndrome type 2B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0000022

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.33

PROVEAN

Benign

0.10

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Pathogenic

0.0

Polyphen

0.0080

Vest4

0.10

MPC

0.25

ClinPred

0.020

GERP RS

2.8

gMVP

0.10

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