rs35010052

Variant names:

• chr2-201287900-T-TA
• rs35010052
• ENST00000696069.1:c.1259+2583_1259+2584insA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000696069.1(CASP8):​c.1259+2583_1259+2584insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00973 in 152,284 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0097 (5 hom., cov: 32)
• Consequence: CASP8 ENST00000696069.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.336
• Publications: 2 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00973 (1481/152284) while in subpopulation NFE AF = 0.0141 (961/68026). AF 95% confidence interval is 0.0134. There are 5 homozygotes in GnomAd4. There are 735 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	NM_001372051.1	MANE Select	c.*1306_*1307insA		downstream_gene	N/A	NP_001358980.1	Q14790-1
	CASP8	NM_001080125.2		c.*1306_*1307insA		downstream_gene	N/A	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.*1306_*1307insA		downstream_gene	N/A	NP_001387571.1	A0A8Q3SID9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000696069.1		c.1259+2583_1259+2584insA		intron	N/A	ENSP00000512371.1	A0A8Q3WKY8
	CASP8	ENST00000673742.1	MANE Select	c.*1306_*1307insA		downstream_gene	N/A	ENSP00000501268.1	Q14790-1
	CASP8	ENST00000358485.8	TSL:1	c.*1306_*1307insA		downstream_gene	N/A	ENSP00000351273.4	Q14790-9

Frequencies

GnomAD3 genomes AF: 0.00974 AC: 1482 AN: 152166 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0196

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00718

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

GnomAD4 genome AF: 0.00973 AC: 1481 AN: 152284 Hom.: 5 Cov.: 32 AF XY: 0.00987 AC XY: 735 AN XY: 74466

African (AFR) AF: 0.00325 AC: 135 AN: 41552

American (AMR) AF: 0.00784 AC: 120 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.0196 AC: 208 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0141 AC: 961 AN: 68026

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.0112 Hom.: 2

Bravo AF: 0.00875

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34

Splicing

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

Other links and lift over

dbSNP: rs35010052; hg19: chr2-202152623;