2-201258272-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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

Publications

112 publications found

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 Gene-Disease associations (from GenCC):

autoimmune lymphoproliferative syndrome type 2B
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

CASP8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	Protein
CASP8	NM_001080125.2 link	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 9	NP_001073594.1
CASP8	NM_001400642.1 link	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 8	NP_001387571.1
CASP8	NM_001400665.1 link	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 6	NP_001387594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein
CASP8	ENST00000358485.8 link	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 9	1	ENSP00000351273.4
CASP8	ENST00000437283.5 link	n.41A>G		non_coding_transcript_exon_variant	Exon 1 of 4	1	ENSP00000407378.1
CASP8	ENST00000264275.9 link	c.-26-8189A>G		intron_variant	Intron 2 of 9	1	ENSP00000264275.5

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

GnomAD2 exomes

AF:

0.660

AC:

164673

AN:

249496

AF XY:

0.666

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 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

African (AFR)

AF:

0.565

AC:

18909

AN:

33472

American (AMR)

AF:

0.544

AC:

24315

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

15254

AN:

26132

East Asian (EAS)

AF:

0.699

AC:

27764

AN:

39696

South Asian (SAS)

AF:

0.676

AC:

58291

AN:

86256

European-Finnish (FIN)

AF:

0.650

AC:

34713

AN:

53410

Middle Eastern (MID)

AF:

0.621

AC:

3583

AN:

5768

European-Non Finnish (NFE)

AF:

0.713

AC:

792736

AN:

1111344

Other (OTH)

AF:

0.674

AC:

40719

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

17390

34781

52171

69562

86952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19800

39600

59400

79200

99000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.648

AC:

98265

AN:

151736

Hom.:

32194

Cov.:

AF XY:

0.644

AC XY:

47710

AN XY:

74122

show subpopulations

African (AFR)

AF:

0.577

AC:

23828

AN:

41298

American (AMR)

AF:

0.564

AC:

8600

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.585

AC:

2031

AN:

3470

East Asian (EAS)

AF:

0.707

AC:

3645

AN:

5156

South Asian (SAS)

AF:

0.682

AC:

3275

AN:

4804

European-Finnish (FIN)

AF:

0.646

AC:

6791

AN:

10520

Middle Eastern (MID)

AF:

0.701

AC:

206

AN:

294

European-Non Finnish (NFE)

AF:

0.705

AC:

47919

AN:

67926

Other (OTH)

AF:

0.612

AC:

1288

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1705

3411

5116

6822

8527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

800

1600

2400

3200

4000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.685

Hom.:

131864

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

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 -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29083408) -

Autoimmune lymphoproliferative syndrome type 2B

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

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

PhyloP100

1.7

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

PromoterAI

-0.22

Neutral

(source)

gMVP

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over