chr2-201267384-C-A

Variant names:

• chr2-201267384-C-A
• rs3754934
• NM_001372051.1:c.305+593C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372051.1(CASP8):​c.305+593C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,058 control chromosomes in the GnomAD database, including 1,452 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 0.11 (1452 hom., cov: 32)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.705

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

Our verdict: Benign. The variant received -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 = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.305+593C>A		intron_variant	Intron 2 of 8	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.305+593C>A		intron_variant	Intron 2 of 8		NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16550 AN: 151940 Hom.: 1447 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0522

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.0471

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.109 AC: 16584 AN: 152058 Hom.: 1452 Cov.: 32 AF XY: 0.112 AC XY: 8334 AN XY: 74312

Gnomad4 AFR AF: 0.218 AC: 0.217665 AN: 0.217665

Gnomad4 AMR AF: 0.0522 AC: 0.0521637 AN: 0.0521637

Gnomad4 ASJ AF: 0.0861 AC: 0.0861175 AN: 0.0861175

Gnomad4 EAS AF: 0.210 AC: 0.20954 AN: 0.20954

Gnomad4 SAS AF: 0.282 AC: 0.281652 AN: 0.281652

Gnomad4 FIN AF: 0.0395 AC: 0.0395459 AN: 0.0395459

Gnomad4 NFE AF: 0.0471 AC: 0.0470727 AN: 0.0470727

Gnomad4 OTH AF: 0.101 AC: 0.101326 AN: 0.101326

Alfa AF: 0.0326 Hom.: 27

Bravo AF: 0.112

Asia WGS AF: 0.235 AC: 817 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	0.61
DANN	Benign	0.72
Mutation Taster		=100/0	polymorphism (auto)

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: rs3754934; hg19: chr2-202132107;