chr2-201360013-T-G

Variant names:

• chr2-201360013-T-G
• rs11681616
• ENST00000696069.1:c.1260-1476T>G

Variant summary

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

The ENST00000696069.1(CASP8):​c.1260-1476T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 151,726 control chromosomes in the GnomAD database, including 14,131 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 0.42 (14131 hom., cov: 31)
• Consequence: CASP8 ENST00000696069.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.597
• Publications: 1 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]

FLACC1 (HGNC:14439): (flagellum associated containing coiled-coil domains 1) Predicted to be located in cytoplasmic vesicle and sperm flagellum. Predicted to be active in cytoplasm; outer dense fiber; and sperm fibrous sheath. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLACC1	XM_024452696.2	c.-48+2581A>C		intron_variant	Intron 2 of 15		XP_024308464.1
FLACC1	XM_047443393.1	c.-48+2581A>C		intron_variant	Intron 2 of 15		XP_047299349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000696069.1	c.1260-1476T>G		intron_variant	Intron 6 of 6			ENSP00000512371.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63647 AN: 151622 Hom.: 14137 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.396

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

GnomAD4 genome AF: 0.419 AC: 63648 AN: 151726 Hom.: 14131 Cov.: 31 AF XY: 0.421 AC XY: 31214 AN XY: 74106

African (AFR) AF: 0.271 AC: 11226 AN: 41368

American (AMR) AF: 0.359 AC: 5479 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1436 AN: 3464

East Asian (EAS) AF: 0.477 AC: 2461 AN: 5162

South Asian (SAS) AF: 0.539 AC: 2592 AN: 4810

European-Finnish (FIN) AF: 0.532 AC: 5568 AN: 10458

Middle Eastern (MID) AF: 0.431 AC: 125 AN: 290

European-Non Finnish (NFE) AF: 0.494 AC: 33545 AN: 67914

Other (OTH) AF: 0.395 AC: 832 AN: 2104

Alfa AF: 0.456 Hom.: 6949

Bravo AF: 0.400

Asia WGS AF: 0.489 AC: 1703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.41
DANN	Benign	0.59
PhyloP100		-0.60

Splicing

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

Other links and lift over

dbSNP: rs11681616; hg19: chr2-202224736;