rs7608692

Variant names:

• chr2-201246236-G-A
• rs7608692
• ENST00000264275.9:c.-27+12124G>A

Variant summary

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

The NM_001228.5(CASP8):​c.-27+12124G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,114 control chromosomes in the GnomAD database, including 3,449 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 0.21 (3449 hom., cov: 32)
• Consequence: CASP8 NM_001228.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.331
• Publications: 13 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 (SAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001228.5. 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_001228.5		c.-27+12124G>A		intron	N/A	NP_001219.2
	CASP8	NM_001400648.1		c.-27+12124G>A		intron	N/A	NP_001387577.1
	CASP8	NM_001400651.1		c.-27+12124G>A		intron	N/A	NP_001387580.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000264275.9	TSL:1	c.-27+12124G>A		intron	N/A	ENSP00000264275.5
	CASP8	ENST00000392258.7	TSL:1	c.-27+12124G>A		intron	N/A	ENSP00000376087.3
	CASP8	ENST00000471383.5	TSL:1	n.250+12124G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31443 AN: 151996 Hom.: 3452 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.200

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

GnomAD4 genome AF: 0.207 AC: 31434 AN: 152114 Hom.: 3449 Cov.: 32 AF XY: 0.210 AC XY: 15646 AN XY: 74364

African (AFR) AF: 0.149 AC: 6187 AN: 41488

American (AMR) AF: 0.168 AC: 2574 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 963 AN: 3470

East Asian (EAS) AF: 0.293 AC: 1517 AN: 5172

South Asian (SAS) AF: 0.316 AC: 1522 AN: 4816

European-Finnish (FIN) AF: 0.292 AC: 3089 AN: 10580

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14908 AN: 67982

Other (OTH) AF: 0.196 AC: 414 AN: 2112

Alfa AF: 0.217 Hom.: 1442

Bravo AF: 0.193

Asia WGS AF: 0.298 AC: 1038 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.2
DANN	Benign	0.69
PhyloP100		-0.33
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: rs7608692; hg19: chr2-202110959;