chr2-201263224-A-C

Variant names:

• chr2-201263224-A-C
• rs6435074
• NM_001372051.1:c.-27+2611A>C

Variant summary

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

The NM_001372051.1(CASP8):​c.-27+2611A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 152,044 control chromosomes in the GnomAD database, including 40,679 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 0.73 (40679 hom., cov: 32)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.287
• Publications: 16 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.809 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.-27+2611A>C		intron	N/A	NP_001358980.1
	CASP8	NM_001080125.2		c.152-3237A>C		intron	N/A	NP_001073594.1
	CASP8	NM_001400642.1		c.152-3237A>C		intron	N/A	NP_001387571.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000673742.1	MANE Select	c.-27+2611A>C		intron	N/A	ENSP00000501268.1
	CASP8	ENST00000358485.8	TSL:1	c.152-3237A>C		intron	N/A	ENSP00000351273.4
	CASP8	ENST00000264275.9	TSL:1	c.-26-3237A>C		intron	N/A	ENSP00000264275.5

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110662 AN: 151926 Hom.: 40640 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.728 AC: 110748 AN: 152044 Hom.: 40679 Cov.: 32 AF XY: 0.725 AC XY: 53868 AN XY: 74332

African (AFR) AF: 0.777 AC: 32198 AN: 41448

American (AMR) AF: 0.580 AC: 8840 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2199 AN: 3470

East Asian (EAS) AF: 0.711 AC: 3692 AN: 5192

South Asian (SAS) AF: 0.830 AC: 3996 AN: 4814

European-Finnish (FIN) AF: 0.686 AC: 7251 AN: 10566

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.738 AC: 50194 AN: 67988

Other (OTH) AF: 0.687 AC: 1453 AN: 2116

Alfa AF: 0.723 Hom.: 14523

Bravo AF: 0.719

Asia WGS AF: 0.799 AC: 2779 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.2
DANN	Benign	0.59
PhyloP100		-0.29
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: rs6435074; hg19: chr2-202127947;