2-201284866-G-C

Variant names:

• chr2-201284866-G-C
• rs1045485
• NM_001372051.1:c.853G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.867
• Publications: 264 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 7762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.853G>C	p.Asp285His	missense_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	c.853G>C	p.Asp285His	missense_variant	Exon 8 of 9		NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes AF: 0.0981 AC: 14907 AN: 152028 Hom.: 821 Cov.: 32

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

GnomAD2 exomes AF: 0.0898 AC: 22585 AN: 251456 AF XY: 0.0893

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 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.: 35 AF XY: 0.115 AC XY: 83814 AN XY: 727206

African (AFR) AF: 0.0631 AC: 2114 AN: 33480

American (AMR) AF: 0.0605 AC: 2704 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1641 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0467 AC: 4030 AN: 86256

European-Finnish (FIN) AF: 0.106 AC: 5647 AN: 53418

Middle Eastern (MID) AF: 0.0853 AC: 492 AN: 5768

European-Non Finnish (NFE) AF: 0.133 AC: 148131 AN: 1111928

Other (OTH) AF: 0.110 AC: 6644 AN: 60384

GnomAD4 genome AF: 0.0982 AC: 14942 AN: 152146 Hom.: 826 Cov.: 32 AF XY: 0.0947 AC XY: 7048 AN XY: 74394

African (AFR) AF: 0.0678 AC: 2810 AN: 41470

American (AMR) AF: 0.0864 AC: 1321 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0386 AC: 186 AN: 4824

European-Finnish (FIN) AF: 0.0981 AC: 1039 AN: 10588

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8874 AN: 68010

Other (OTH) AF: 0.107 AC: 226 AN: 2114

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:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19843670, 19214744, 19203830, 19318553, 20176653, 16251207, 18398042, 20978178, 20502973, 17293864, 25502557, 20033885, 15601643, 28674227, 22588838)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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.

Autoimmune lymphoproliferative syndrome type 2B Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 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.

not specified Benign:1

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: MAF

BREAST CANCER, PROTECTION AGAINST Benign:1

Mar 01, 2007

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.58
DANN	Benign	0.41
DEOGEN2	Benign	0.0	.;T;.;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.097	N
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	T
MutationAssessor	Benign	0.0	.;L;.;.;.;.
PhyloP100		-0.87
PrimateAI	Benign	0.26	T
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
Vest4		0.054
ClinPred		0.0036	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.44
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1045485; hg19: chr2-202149589; COSMIC: COSV51850733; COSMIC: COSV51850733;