ENST00000264275.9:c.-27+421T>G

Variant names:

• chr2-201234533-T-G
• rs12620010
• ENST00000264275.9:c.-27+421T>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+421T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 151,822 control chromosomes in the GnomAD database, including 12,995 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 0.40 (12995 hom., cov: 30)
• Consequence: CASP8 ENST00000264275.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.641
• Publications: 6 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 = 0.481 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.-27+421T>G		intron	N/A	NP_001219.2
	CASP8	NM_001400648.1		c.-27+421T>G		intron	N/A	NP_001387577.1
	CASP8	NM_001400651.1		c.-27+421T>G		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.-27+421T>G		intron	N/A	ENSP00000264275.5
	CASP8	ENST00000392258.7	TSL:1	c.-27+421T>G		intron	N/A	ENSP00000376087.3
	CASP8	ENST00000471383.5	TSL:1	n.250+421T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61198 AN: 151704 Hom.: 12997 Cov.: 30

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.429

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

GnomAD4 genome AF: 0.403 AC: 61194 AN: 151822 Hom.: 12995 Cov.: 30 AF XY: 0.396 AC XY: 29399 AN XY: 74178

African (AFR) AF: 0.295 AC: 12229 AN: 41404

American (AMR) AF: 0.383 AC: 5848 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1576 AN: 3462

East Asian (EAS) AF: 0.222 AC: 1149 AN: 5170

South Asian (SAS) AF: 0.241 AC: 1158 AN: 4802

European-Finnish (FIN) AF: 0.465 AC: 4877 AN: 10498

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 32985 AN: 67912

Other (OTH) AF: 0.429 AC: 903 AN: 2106

Alfa AF: 0.443 Hom.: 1908

Bravo AF: 0.397

Asia WGS AF: 0.222 AC: 774 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	1.7
DANN	Benign	0.48
PhyloP100		-0.64
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: rs12620010; hg19: chr2-202099256;