2-201287439-T-A

Variant names:

• chr2-201287439-T-A
• rs13113
• NM_001372051.1:c.*845T>A

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.*845T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 154,542 control chromosomes in the GnomAD database, including 10,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10138 hom., cov: 32)
  • Exomes 𝑓: 0.34 (166 hom.)
• Consequence: CASP8 NM_001372051.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.71
• Publications: 24 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-201287439-T-A is Benign according to our data. Variant chr2-201287439-T-A is described in ClinVar as Benign. ClinVar VariationId is 333525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.*845T>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.*845T>A		3_prime_UTR_variant	Exon 9 of 9		NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50996 AN: 151888 Hom.: 10142 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.319

GnomAD4 exome AF: 0.340 AC: 863 AN: 2536 Hom.: 166 Cov.: 0 AF XY: 0.346 AC XY: 450 AN XY: 1302

African (AFR) AF: 0.162 AC: 12 AN: 74

American (AMR) AF: 0.125 AC: 1 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.359 AC: 33 AN: 92

European-Finnish (FIN) AF: 0.485 AC: 197 AN: 406

Middle Eastern (MID) AF: 0.308 AC: 491 AN: 1592

European-Non Finnish (NFE) AF: 0.483 AC: 87 AN: 180

Other (OTH) AF: 0.228 AC: 41 AN: 180

GnomAD4 genome AF: 0.335 AC: 50980 AN: 152006 Hom.: 10138 Cov.: 32 AF XY: 0.337 AC XY: 25005 AN XY: 74290

African (AFR) AF: 0.112 AC: 4631 AN: 41504

American (AMR) AF: 0.322 AC: 4920 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1277 AN: 3472

East Asian (EAS) AF: 0.481 AC: 2486 AN: 5172

South Asian (SAS) AF: 0.342 AC: 1645 AN: 4808

European-Finnish (FIN) AF: 0.474 AC: 4985 AN: 10522

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29912 AN: 67934

Other (OTH) AF: 0.318 AC: 672 AN: 2110

Alfa AF: 0.376 Hom.: 1447

Bravo AF: 0.318

Asia WGS AF: 0.380 AC: 1321 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.23
DANN	Benign	0.38
PhyloP100		-1.7
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: rs13113; hg19: chr2-202152162;