2-201258233-T-C

Variant names:

• chr2-201258233-T-C
• rs3769824
• ENST00000358485.8:c.2T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PVS1_Supporting BP6_Very_Strong BA1

The ENST00000358485.8(CASP8):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,607,054 control chromosomes in the GnomAD database, including 2,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (182 hom., cov: 31)
  • Exomes 𝑓: 0.045 (1854 hom.)
• Consequence: CASP8 ENST00000358485.8 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.196
• Publications: 18 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 -15 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 43 codons. Genomic position: 201258358. Lost 0.079 part of the original CDS.
• BP6: Variant 2-201258233-T-C is Benign according to our data. Variant chr2-201258233-T-C is described in ClinVar as Benign. ClinVar VariationId is 402493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001080125.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 9		NP_001073594.1
CASP8	NM_001400642.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 8		NP_001387571.1
CASP8	NM_001400665.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 6		NP_001387594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000358485.8	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	1		ENSP00000351273.4
CASP8	ENST00000437283.5	n.2T>C		non_coding_transcript_exon_variant	Exon 1 of 4	1		ENSP00000407378.1
CASP8	ENST00000264275.9	c.-26-8228T>C		intron_variant	Intron 2 of 9	1		ENSP00000264275.5

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5565 AN: 151150 Hom.: 182 Cov.: 31

Gnomad AFR AF: 0.00867

Gnomad AMI AF: 0.0166

Gnomad AMR AF: 0.0693

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0388

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0322

GnomAD2 exomes AF: 0.0490 AC: 12206 AN: 249222 AF XY: 0.0464

Gnomad AFR exome AF: 0.00698

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00167

Gnomad FIN exome AF: 0.0742

Gnomad NFE exome AF: 0.0409

Gnomad OTH exome AF: 0.0429

GnomAD4 exome AF: 0.0452 AC: 65840 AN: 1455786 Hom.: 1854 Cov.: 30 AF XY: 0.0445 AC XY: 32240 AN XY: 724272

African (AFR) AF: 0.00652 AC: 218 AN: 33448

American (AMR) AF: 0.117 AC: 5212 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 354 AN: 26046

East Asian (EAS) AF: 0.00383 AC: 152 AN: 39694

South Asian (SAS) AF: 0.0427 AC: 3683 AN: 86238

European-Finnish (FIN) AF: 0.0701 AC: 3738 AN: 53336

Middle Eastern (MID) AF: 0.0176 AC: 101 AN: 5752

European-Non Finnish (NFE) AF: 0.0451 AC: 49914 AN: 1106600

Other (OTH) AF: 0.0410 AC: 2468 AN: 60142

GnomAD4 genome AF: 0.0368 AC: 5567 AN: 151268 Hom.: 182 Cov.: 31 AF XY: 0.0381 AC XY: 2815 AN XY: 73942

African (AFR) AF: 0.00864 AC: 357 AN: 41322

American (AMR) AF: 0.0692 AC: 1046 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3458

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5170

South Asian (SAS) AF: 0.0390 AC: 186 AN: 4768

European-Finnish (FIN) AF: 0.0781 AC: 826 AN: 10570

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0444 AC: 2997 AN: 67558

Other (OTH) AF: 0.0319 AC: 67 AN: 2100

Alfa AF: 0.0378 Hom.: 475

Bravo AF: 0.0350

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0439 AC: 169

ESP6500AA AF: 0.00898 AC: 34

ESP6500EA AF: 0.0437 AC: 361

ExAC AF: 0.0453 AC: 5479

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.0393

EpiControl AF: 0.0388

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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: Frequency in ESP (all): 395/12046= 3.27% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.5
DANN	Benign	0.68
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00090	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.91	T
PhyloP100		-0.20
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.083
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.028
ClinPred		0.019	T
GERP RS		0.58
PromoterAI		0.12	Neutral
gMVP		0.17
Mutation Taster		=164/36	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3769824; hg19: chr2-202122956; COSMIC: COSV99965599;