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
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372051.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	NM_001372051.1	MANE Select	c.305+593C>A		intron	N/A	NP_001358980.1	Q14790-1
	CASP8	NM_001080125.2		c.482+593C>A		intron	N/A	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.482+593C>A		intron	N/A	NP_001387571.1	A0A8Q3SID9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000673742.1	MANE Select	c.305+593C>A		intron	N/A	ENSP00000501268.1	Q14790-1
	CASP8	ENST00000358485.8	TSL:1	c.482+593C>A		intron	N/A	ENSP00000351273.4	Q14790-9
	CASP8	ENST00000264275.9	TSL:1	c.305+593C>A		intron	N/A	ENSP00000264275.5	Q14790-4

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

African (AFR) AF: 0.218 AC: 9017 AN: 41426

American (AMR) AF: 0.0522 AC: 798 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 299 AN: 3472

East Asian (EAS) AF: 0.210 AC: 1085 AN: 5178

South Asian (SAS) AF: 0.282 AC: 1357 AN: 4818

European-Finnish (FIN) AF: 0.0395 AC: 418 AN: 10570

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0471 AC: 3200 AN: 67980

Other (OTH) AF: 0.101 AC: 214 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.61
DANN	Benign	0.72
PhyloP100		-0.70
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

Other links and lift over

dbSNP: rs3754934; hg19: chr2-202132107;