2-201258233-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 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:2
• Conservation: PhyloP100: -0.196

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 2-201258233-T-C is Benign according to our data. Variant chr2-201258233-T-C is described in ClinVar as [Benign]. Clinvar id is 402493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201258233-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CASP8	NM_001080125.2	c.2T>C	p.Met1?	start_lost	1/9
CASP8	NM_001400642.1	c.2T>C	p.Met1?	start_lost	1/8
CASP8	NM_001400665.1	c.2T>C	p.Met1?	start_lost	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000358485.8	c.2T>C	p.Met1?	start_lost	1/9	1
CASP8	ENST00000264275.9	c.-26-8228T>C		intron_variant		1
CASP8	ENST00000392258.7	c.-26-8228T>C		intron_variant		1

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

GnomAD3 exomes AF: 0.0490 AC: 12206 AN: 249222 Hom.: 489 AF XY: 0.0464 AC XY: 6270 AN XY: 135188

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 SAS exome AF: 0.0425

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

Gnomad4 AFR exome AF: 0.00652

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.00383

Gnomad4 SAS exome AF: 0.0427

Gnomad4 FIN exome AF: 0.0701

Gnomad4 NFE exome AF: 0.0451

Gnomad4 OTH exome AF: 0.0410

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

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.0692

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0390

Gnomad4 FIN AF: 0.0781

Gnomad4 NFE AF: 0.0444

Gnomad4 OTH AF: 0.0319

Alfa AF: 0.0362 Hom.: 208

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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% -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2018

- -

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
MutationTaster	Benign	0.99	D;N;N;N;N;N;N
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
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs3769824; hg19: chr2-202122956; COSMIC: COSV99965599; COSMIC: COSV99965599;