2-201287768-T-A

Variant names:

• chr2-201287768-T-A
• rs1035140
• ENST00000696069.1:c.1259+2451T>A

Variant summary

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

The ENST00000696069.1(CASP8):​c.1259+2451T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 152,030 control chromosomes in the GnomAD database, including 16,737 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 0.46 (16734 hom., cov: 32)
  • Exomes 𝑓: 0.75 (3 hom.)
• Consequence: CASP8 ENST00000696069.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 14 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=-0.64).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000696069.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	NM_001372051.1	MANE Select	c.*1174T>A		downstream_gene	N/A	NP_001358980.1
	CASP8	NM_001080125.2		c.*1174T>A		downstream_gene	N/A	NP_001073594.1
	CASP8	NM_001400642.1		c.*1174T>A		downstream_gene	N/A	NP_001387571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000696069.1		c.1259+2451T>A		intron	N/A	ENSP00000512371.1
	CASP8	ENST00000673742.1	MANE Select	c.*1174T>A		downstream_gene	N/A	ENSP00000501268.1
	CASP8	ENST00000358485.8	TSL:1	c.*1174T>A		downstream_gene	N/A	ENSP00000351273.4

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69924 AN: 151900 Hom.: 16737 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.750 AC: 9 AN: 12 Hom.: 3 AF XY: 1.00 AC XY: 2 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 9 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.460 AC: 69921 AN: 152018 Hom.: 16734 Cov.: 32 AF XY: 0.458 AC XY: 34016 AN XY: 74306

African (AFR) AF: 0.333 AC: 13817 AN: 41460

American (AMR) AF: 0.416 AC: 6347 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1654 AN: 3468

East Asian (EAS) AF: 0.489 AC: 2531 AN: 5174

South Asian (SAS) AF: 0.409 AC: 1974 AN: 4826

European-Finnish (FIN) AF: 0.523 AC: 5507 AN: 10530

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36661 AN: 67972

Other (OTH) AF: 0.428 AC: 903 AN: 2108

Alfa AF: 0.498 Hom.: 2303

Bravo AF: 0.448

Asia WGS AF: 0.438 AC: 1524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		1.4
Mutation Taster		=97/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1035140; hg19: chr2-202152491;