2-201258272-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000358485.8(CASP8):c.41A>G(p.Lys14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,612,910 control chromosomes in the GnomAD database, including 387,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32194 hom., cov: 29)
  • Exomes 𝑓: 0.70 (355271 hom.)
• Consequence: CASP8 ENST00000358485.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.73

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.249959E-6).
• BP6: Variant 2-201258272-A-G is Benign according to our data. Variant chr2-201258272-A-G is described in ClinVar as [Benign]. Clinvar id is 402492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001080125.2	c.41A>G	p.Lys14Arg	missense_variant	1/9
CASP8	NM_001400642.1	c.41A>G	p.Lys14Arg	missense_variant	1/8
CASP8	NM_001400665.1	c.41A>G	p.Lys14Arg	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000358485.8	c.41A>G	p.Lys14Arg	missense_variant	1/9	1
CASP8	ENST00000264275.9	c.-26-8189A>G		intron_variant		1
CASP8	ENST00000392258.7	c.-26-8189A>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98187 AN: 151618 Hom.: 32170 Cov.: 29

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.749

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.610

GnomAD3 exomes AF: 0.660 AC: 164673 AN: 249496 Hom.: 54987 AF XY: 0.666 AC XY: 90116 AN XY: 135366

Gnomad AFR exome AF: 0.576

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.577

Gnomad EAS exome AF: 0.710

Gnomad SAS exome AF: 0.680

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.706

Gnomad OTH exome AF: 0.647

GnomAD4 exome AF: 0.696 AC: 1016284 AN: 1461174 Hom.: 355271 Cov.: 50 AF XY: 0.695 AC XY: 505524 AN XY: 726898

Gnomad4 AFR exome AF: 0.565

Gnomad4 AMR exome AF: 0.544

Gnomad4 ASJ exome AF: 0.584

Gnomad4 EAS exome AF: 0.699

Gnomad4 SAS exome AF: 0.676

Gnomad4 FIN exome AF: 0.650

Gnomad4 NFE exome AF: 0.713

Gnomad4 OTH exome AF: 0.674

GnomAD4 genome AF: 0.648 AC: 98265 AN: 151736 Hom.: 32194 Cov.: 29 AF XY: 0.644 AC XY: 47710 AN XY: 74122

Gnomad4 AFR AF: 0.577

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.707

Gnomad4 SAS AF: 0.682

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.705

Gnomad4 OTH AF: 0.612

Alfa AF: 0.690 Hom.: 91334

Bravo AF: 0.637

TwinsUK AF: 0.723 AC: 2680

ALSPAC AF: 0.724 AC: 2791

ESP6500AA AF: 0.592 AC: 2286

ESP6500EA AF: 0.706 AC: 5832

ExAC AF: 0.667 AC: 80598

Asia WGS AF: 0.684 AC: 2380 AN: 3478

EpiCase AF: 0.692

EpiControl AF: 0.702

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 80% of patients studied by a panel of primary immunodeficiencies. Number of patients: 77. Only high quality variants are reported. -
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 -

Autoimmune lymphoproliferative syndrome type 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2018

This variant is associated with the following publications: (PMID: 29083408) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	13
Dann	Benign	0.97
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0080	B
Vest4		0.10
MPC		0.25
ClinPred		0.020	T
GERP RS		2.8
gMVP		0.10

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

Other links and lift over

dbSNP: rs3769823; hg19: chr2-202122995; COSMIC: COSV51848843; COSMIC: COSV51848843;