2-201246236-G-A

Position:

• chr2-201246236-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000264275.9(CASP8):​c.-27+12124G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,114 control chromosomes in the GnomAD database, including 3,449 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3449 hom., cov: 32)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.331

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001080124.2	c.-27+12124G>A		intron_variant
CASP8	NM_001228.4	c.-27+12124G>A		intron_variant
CASP8	NM_001400648.1	c.-27+12124G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000264275.9	c.-27+12124G>A		intron_variant		1
CASP8	ENST00000392258.7	c.-27+12124G>A		intron_variant		1
CASP8	ENST00000471383.5	n.250+12124G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31443 AN: 151996 Hom.: 3452 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.200

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.207 AC: 31434 AN: 152114 Hom.: 3449 Cov.: 32 AF XY: 0.210 AC XY: 15646 AN XY: 74364

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.196

Alfa AF: 0.215 Hom.: 816

Bravo AF: 0.193

Asia WGS AF: 0.298 AC: 1038 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.2
DANN	Benign	0.69

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7608692; hg19: chr2-202110959;