rs1045487

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001372051.1(CASP8):c.960G>A(p.Lys320Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,613,906 control chromosomes in the GnomAD database, including 7,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1334 hom., cov: 32)

Exomes 𝑓: 0.069 ( 6522 hom. )

Consequence

CASP8
NM_001372051.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.321

Publications

30 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 2-201284973-G-A is Benign according to our data. Variant chr2-201284973-G-A is described in ClinVar as Benign. ClinVar VariationId is 333505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.321 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001372051.1 link	c.960G>A	p.Lys320Lys	synonymous_variant	Exon 8 of 9	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1 link	c.960G>A	p.Lys320Lys	synonymous_variant	Exon 8 of 9		NM_001372051.1	ENSP00000501268.1		Q14790-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15765

AN:

151950

Hom.:

1326

Cov.:

show subpopulations

Gnomad AFR

AF:

0.209

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.0389

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.0948

AC:

23830

AN:

251464

AF XY:

0.101

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.0292

Gnomad ASJ exome

AF:

0.0840

Gnomad EAS exome

AF:

0.196

Gnomad FIN exome

AF:

0.0399

Gnomad NFE exome

AF:

0.0490

Gnomad OTH exome

AF:

0.0698

GnomAD4 exome

AF:

0.0692

AC:

101220

AN:

1461836

Hom.:

6522

Cov.:

AF XY:

0.0747

AC XY:

54313

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.220

AC:

7377

AN:

33474

American (AMR)

AF:

0.0327

AC:

1462

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0846

AC:

2211

AN:

26136

East Asian (EAS)

AF:

0.226

AC:

8958

AN:

39700

South Asian (SAS)

AF:

0.251

AC:

21680

AN:

86254

European-Finnish (FIN)

AF:

0.0409

AC:

2186

AN:

53418

Middle Eastern (MID)

AF:

0.148

AC:

853

AN:

5768

European-Non Finnish (NFE)

AF:

0.0463

AC:

51500

AN:

1111966

Other (OTH)

AF:

0.0827

AC:

4993

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

5820

11640

17459

23279

29099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2260

4520

6780

9040

11300

<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:

0.104

AC:

15805

AN:

152070

Hom.:

1334

Cov.:

AF XY:

0.107

AC XY:

7946

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.209

AC:

8667

AN:

41400

American (AMR)

AF:

0.0493

AC:

753

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

284

AN:

3472

East Asian (EAS)

AF:

0.201

AC:

1040

AN:

5176

South Asian (SAS)

AF:

0.260

AC:

1253

AN:

4812

European-Finnish (FIN)

AF:

0.0389

AC:

412

AN:

10586

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0452

AC:

3073

AN:

68018

Other (OTH)

AF:

0.102

AC:

215

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

651

1303

1954

2606

3257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<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:

0.0615

Hom.:

1333

Bravo

AF:

0.107

Asia WGS

AF:

0.227

AC:

789

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.0

(source)

DANN

Benign

0.69

PhyloP100

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

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