rs36043647

Variant names:

• chr2-201277115-T-C
• rs36043647
• NM_001372051.1:c.802+147T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001372051.1(CASP8):​c.802+147T>C variant causes a intron 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_001372051.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.294
• Publications: 8 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

ENSG00000289698 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.802+147T>C		intron_variant	Intron 7 of 8	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.802+147T>C		intron_variant	Intron 7 of 8		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

African (AFR) AF: 0.00980 AC: 121 AN: 12344

American (AMR) AF: 0.0429 AC: 762 AN: 17760

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 749 AN: 15118

East Asian (EAS) AF: 0.000100 AC: 3 AN: 29944

South Asian (SAS) AF: 0.0431 AC: 1856 AN: 43108

European-Finnish (FIN) AF: 0.0414 AC: 1609 AN: 38876

Middle Eastern (MID) AF: 0.0892 AC: 182 AN: 2040

European-Non Finnish (NFE) AF: 0.0640 AC: 18043 AN: 281864

Other (OTH) AF: 0.0541 AC: 1408 AN: 26004

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

African (AFR) AF: 0.0101 AC: 419 AN: 41570

American (AMR) AF: 0.0386 AC: 591 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.0305 AC: 147 AN: 4822

European-Finnish (FIN) AF: 0.0340 AC: 361 AN: 10604

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0616 AC: 4191 AN: 68030

Other (OTH) AF: 0.0441 AC: 93 AN: 2110

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.9
DANN	Benign	0.82
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs36043647; hg19: chr2-202141838;