2-201360013-T-G

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
FLACC1	XM_024452696.2	c.-48+2581A>C		intron_variant
FLACC1	XM_047443393.1	c.-48+2581A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000696069.1	c.1260-1476T>G		intron_variant

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

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.477

Gnomad4 SAS AF: 0.539

Gnomad4 FIN AF: 0.532

Gnomad4 NFE AF: 0.494

Gnomad4 OTH AF: 0.395

Alfa AF: 0.427 Hom.: 3460

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11681616; hg19: chr2-202224736;