chr2-201258707-C-T

Variant names:

• chr2-201258707-C-T
• rs3769821
• ENST00000358485.8:c.151+325C>T

Variant summary

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

The NM_001080125.2(CASP8):​c.151+325C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 151,986 control chromosomes in the GnomAD database, including 26,078 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 0.57 (26078 hom., cov: 31)
• Consequence: CASP8 NM_001080125.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.710
• Publications: 38 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080125.2. 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_001080125.2		c.151+325C>T		intron	N/A	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.151+325C>T		intron	N/A	NP_001387571.1	A0A8Q3SID9
	CASP8	NM_001228.5		c.-26-7754C>T		intron	N/A	NP_001219.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000358485.8	TSL:1	c.151+325C>T		intron	N/A	ENSP00000351273.4	Q14790-9
	CASP8	ENST00000264275.9	TSL:1	c.-26-7754C>T		intron	N/A	ENSP00000264275.5	Q14790-4
	CASP8	ENST00000392258.7	TSL:1	c.-26-7754C>T		intron	N/A	ENSP00000376087.3	Q14790-5

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87209 AN: 151868 Hom.: 26080 Cov.: 31

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.558

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

GnomAD4 genome AF: 0.574 AC: 87224 AN: 151986 Hom.: 26078 Cov.: 31 AF XY: 0.571 AC XY: 42411 AN XY: 74278

African (AFR) AF: 0.417 AC: 17279 AN: 41448

American (AMR) AF: 0.500 AC: 7643 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1873 AN: 3470

East Asian (EAS) AF: 0.698 AC: 3607 AN: 5164

South Asian (SAS) AF: 0.632 AC: 3043 AN: 4814

European-Finnish (FIN) AF: 0.611 AC: 6440 AN: 10542

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45315 AN: 67960

Other (OTH) AF: 0.555 AC: 1168 AN: 2104

Alfa AF: 0.642 Hom.: 53384

Bravo AF: 0.560

Asia WGS AF: 0.641 AC: 2229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.63
DANN	Benign	0.88
PhyloP100		-0.71
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: rs3769821; hg19: chr2-202123430;