2-201246657-A-G

Variant names:

• chr2-201246657-A-G
• rs3769825
• ENST00000264275.9:c.-27+12545A>G

Variant summary

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

The ENST00000264275.9(CASP8):​c.-27+12545A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,882 control chromosomes in the GnomAD database, including 16,748 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 (16748 hom., cov: 31)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.493
• Publications: 53 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001228.5	c.-27+12545A>G		intron_variant	Intron 2 of 9		NP_001219.2
CASP8	NM_001400648.1	c.-27+12545A>G		intron_variant	Intron 2 of 9		NP_001387577.1
CASP8	NM_001400651.1	c.-27+12545A>G		intron_variant	Intron 2 of 9		NP_001387580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000264275.9	c.-27+12545A>G		intron_variant	Intron 2 of 9	1		ENSP00000264275.5
CASP8	ENST00000392258.7	c.-27+12545A>G		intron_variant	Intron 2 of 7	1		ENSP00000376087.3
CASP8	ENST00000471383.5	n.250+12545A>G		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69625 AN: 151764 Hom.: 16734 Cov.: 31

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.459

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

GnomAD4 genome AF: 0.459 AC: 69671 AN: 151882 Hom.: 16748 Cov.: 31 AF XY: 0.449 AC XY: 33339 AN XY: 74234

African (AFR) AF: 0.367 AC: 15203 AN: 41392

American (AMR) AF: 0.439 AC: 6695 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1355 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1060 AN: 5156

South Asian (SAS) AF: 0.267 AC: 1287 AN: 4820

European-Finnish (FIN) AF: 0.493 AC: 5199 AN: 10542

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.551 AC: 37412 AN: 67950

Other (OTH) AF: 0.460 AC: 967 AN: 2104

Alfa AF: 0.515 Hom.: 73662

Bravo AF: 0.454

Asia WGS AF: 0.248 AC: 864 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	0.31
DANN	Benign	0.66
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3769825; hg19: chr2-202111380;