2-201286440-A-G

Position:

• chr2-201286440-A-G

Variant summary

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

The NM_001372051.1(CASP8):​c.1305-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,605,558 control chromosomes in the GnomAD database, including 423,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39792 hom., cov: 31)
  • Exomes 𝑓: 0.72 (383827 hom.)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.314

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 (BayesDel_noAF=-0.9).
• BP6: Variant 2-201286440-A-G is Benign according to our data. Variant chr2-201286440-A-G is described in ClinVar as [Benign]. Clinvar id is 1168127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201286440-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.1305-19A>G		intron_variant		ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.1305-19A>G		intron_variant			NM_001372051.1	ENSP00000501268	P1

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109397 AN: 151906 Hom.: 39753 Cov.: 31

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.676

GnomAD3 exomes AF: 0.701 AC: 175720 AN: 250534 Hom.: 62624 AF XY: 0.710 AC XY: 96282 AN XY: 135514

Gnomad AFR exome AF: 0.788

Gnomad AMR exome AF: 0.531

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.705

Gnomad SAS exome AF: 0.825

Gnomad FIN exome AF: 0.673

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.685

GnomAD4 exome AF: 0.725 AC: 1053181 AN: 1453536 Hom.: 383827 Cov.: 34 AF XY: 0.727 AC XY: 526293 AN XY: 723536

Gnomad4 AFR exome AF: 0.783

Gnomad4 AMR exome AF: 0.539

Gnomad4 ASJ exome AF: 0.619

Gnomad4 EAS exome AF: 0.681

Gnomad4 SAS exome AF: 0.821

Gnomad4 FIN exome AF: 0.673

Gnomad4 NFE exome AF: 0.730

Gnomad4 OTH exome AF: 0.714

GnomAD4 genome AF: 0.720 AC: 109482 AN: 152022 Hom.: 39792 Cov.: 31 AF XY: 0.717 AC XY: 53246 AN XY: 74294

Gnomad4 AFR AF: 0.786

Gnomad4 AMR AF: 0.575

Gnomad4 ASJ AF: 0.624

Gnomad4 EAS AF: 0.698

Gnomad4 SAS AF: 0.827

Gnomad4 FIN AF: 0.665

Gnomad4 NFE AF: 0.721

Gnomad4 OTH AF: 0.677

Alfa AF: 0.715 Hom.: 14607

Bravo AF: 0.713

Asia WGS AF: 0.788 AC: 2741 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

not specified Benign:1

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 82% of patients studied by a panel of primary immunodeficiencies. Number of patients: 79. Only high quality variants are reported. -

Autoimmune lymphoproliferative syndrome type 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.1
DANN	Benign	0.64

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: rs3769818; hg19: chr2-202151163; COSMIC: COSV51844734; COSMIC: COSV51844734;