rs1045487

Positions:

chr2-201284973-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001372051.1(CASP8):c.960G>A(p.Lys320=) 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

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 -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 id 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/exons	MANE	Protein	UniProt
CASP8	NM_001372051.1 linkuse as main transcript	c.960G>A	p.Lys320=	synonymous_variant	8/9	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1 linkuse as main transcript	c.960G>A	p.Lys320=	synonymous_variant	8/9		NM_001372051.1	ENSP00000501268	P1	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

GnomAD3 exomes

AF:

0.0948

AC:

23830

AN:

251464

Hom.:

2045

AF XY:

0.101

AC XY:

13777

AN XY:

135908

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 SAS exome

AF:

0.260

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

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.0327

Gnomad4 ASJ exome

AF:

0.0846

Gnomad4 EAS exome

AF:

0.226

Gnomad4 SAS exome

AF:

0.251

Gnomad4 FIN exome

AF:

0.0409

Gnomad4 NFE exome

AF:

0.0463

Gnomad4 OTH exome

AF:

0.0827

GnomAD4 genome

AF:

0.104

AC:

15805

AN:

152070

Hom.:

1334

Cov.:

AF XY:

0.107

AC XY:

7946

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.209

Gnomad4 AMR

AF:

0.0493

Gnomad4 ASJ

AF:

0.0818

Gnomad4 EAS

AF:

0.201

Gnomad4 SAS

AF:

0.260

Gnomad4 FIN

AF:

0.0389

Gnomad4 NFE

AF:

0.0452

Gnomad4 OTH

AF:

0.102

Alfa

AF:

0.0599

Hom.:

554

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.0

DANN

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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