rs3754935

Variant names:

• chr2-201254549-A-C
• rs3754935
• ENST00000264275.9:c.-26-11912A>C

Variant summary

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

The ENST00000264275.9(CASP8):​c.-26-11912A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 152,166 control chromosomes in the GnomAD database, including 1,812 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 0.13 (1812 hom., cov: 32)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154
• Publications: 5 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264275.9. 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_001228.5		c.-26-11912A>C		intron	N/A	NP_001219.2
	CASP8	NM_001400648.1		c.-26-11912A>C		intron	N/A	NP_001387577.1
	CASP8	NM_001400651.1		c.-26-11912A>C		intron	N/A	NP_001387580.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000264275.9	TSL:1	c.-26-11912A>C		intron	N/A	ENSP00000264275.5
	CASP8	ENST00000392258.7	TSL:1	c.-26-11912A>C		intron	N/A	ENSP00000376087.3
	CASP8	ENST00000471383.5	TSL:1	n.251-11912A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19832 AN: 152048 Hom.: 1807 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.0775

Gnomad OTH AF: 0.119

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

GnomAD4 genome AF: 0.131 AC: 19870 AN: 152166 Hom.: 1812 Cov.: 32 AF XY: 0.133 AC XY: 9918 AN XY: 74406

African (AFR) AF: 0.234 AC: 9701 AN: 41488

American (AMR) AF: 0.0622 AC: 951 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 329 AN: 3470

East Asian (EAS) AF: 0.228 AC: 1175 AN: 5156

South Asian (SAS) AF: 0.292 AC: 1410 AN: 4822

European-Finnish (FIN) AF: 0.0525 AC: 557 AN: 10614

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.0775 AC: 5273 AN: 68012

Other (OTH) AF: 0.118 AC: 248 AN: 2104

Alfa AF: 0.0959 Hom.: 3309

Bravo AF: 0.134

Asia WGS AF: 0.257 AC: 891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.93
DANN	Benign	0.40
PhyloP100		-0.15
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: rs3754935; hg19: chr2-202119272;