2-201257992-T-G

Position:

• chr2-201257992-T-G

Variant summary

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

The ENST00000264275.9(CASP8):​c.-26-8469T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 507,786 control chromosomes in the GnomAD database, including 1,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (320 hom., cov: 32)
  • Exomes 𝑓: 0.044 (751 hom.)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.121

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-201257992-T-G is Benign according to our data. Variant chr2-201257992-T-G is described in ClinVar as [Benign]. Clinvar id is 1263107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP8	NM_001228.5	c.-26-8469T>G		intron_variant			NP_001219.2
CASP8	NM_001400648.1	c.-26-8469T>G		intron_variant			NP_001387577.1
CASP8	NM_001400651.1	c.-26-8469T>G		intron_variant			NP_001387580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000264275.9	c.-26-8469T>G		intron_variant		1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-26-8469T>G		intron_variant		1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.251-8469T>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 7926 AN: 152146 Hom.: 322 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0459

GnomAD4 exome AF: 0.0439 AC: 15615 AN: 355522 Hom.: 751 Cov.: 3 AF XY: 0.0511 AC XY: 9688 AN XY: 189568

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0376

Gnomad4 EAS exome AF: 0.00308

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.0414

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0369

GnomAD4 genome AF: 0.0521 AC: 7934 AN: 152264 Hom.: 320 Cov.: 32 AF XY: 0.0528 AC XY: 3930 AN XY: 74458

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0269

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.00598

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0268

Gnomad4 OTH AF: 0.0455

Alfa AF: 0.0312 Hom.: 111

Bravo AF: 0.0508

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17860418; hg19: chr2-202122715;