rs36043647

Positions:

• chr2-201277115-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001400679.1(CASP8):​c.*176T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 619,358 control chromosomes in the GnomAD database, including 944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (164 hom., cov: 32)
  • Exomes 𝑓: 0.053 (780 hom.)
• Consequence: CASP8 NM_001400679.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.294

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]

ENSG00000289698 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-201277115-T-C is Benign according to our data. Variant chr2-201277115-T-C is described in ClinVar as [Benign]. Clinvar id is 1265335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.06 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.802+147T>C		intron_variant		ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.802+147T>C		intron_variant			NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6034 AN: 152182 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0305

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0616

Gnomad OTH AF: 0.0445

GnomAD4 exome AF: 0.0530 AC: 24733 AN: 467058 Hom.: 780 Cov.: 5 AF XY: 0.0530 AC XY: 13212 AN XY: 249384

Gnomad4 AFR exome AF: 0.00980

Gnomad4 AMR exome AF: 0.0429

Gnomad4 ASJ exome AF: 0.0495

Gnomad4 EAS exome AF: 0.000100

Gnomad4 SAS exome AF: 0.0431

Gnomad4 FIN exome AF: 0.0414

Gnomad4 NFE exome AF: 0.0640

Gnomad4 OTH exome AF: 0.0541

GnomAD4 genome AF: 0.0396 AC: 6033 AN: 152300 Hom.: 164 Cov.: 32 AF XY: 0.0384 AC XY: 2862 AN XY: 74468

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0386

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0305

Gnomad4 FIN AF: 0.0340

Gnomad4 NFE AF: 0.0616

Gnomad4 OTH AF: 0.0441

Alfa AF: 0.0542 Hom.: 73

Bravo AF: 0.0380

Asia WGS AF: 0.0140 AC: 48 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.9
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs36043647; hg19: chr2-202141838;