2-201275215-G-C

Variant names:

• chr2-201275215-G-C
• rs7571586
• NM_001372051.1:c.660+262G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001372051.1(CASP8):​c.660+262G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0493 in 152,128 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.049 (436 hom., cov: 32)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.674
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-201275215-G-C is Benign according to our data. Variant chr2-201275215-G-C is described in ClinVar as [Benign]. Clinvar id is 1236435.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.660+262G>C		intron_variant	Intron 6 of 8	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.660+262G>C		intron_variant	Intron 6 of 8		NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7492 AN: 152010 Hom.: 438 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00577

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0388

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

GnomAD4 genome AF: 0.0493 AC: 7500 AN: 152128 Hom.: 436 Cov.: 32 AF XY: 0.0498 AC XY: 3703 AN XY: 74378

African (AFR) AF: 0.129 AC: 5359 AN: 41458

American (AMR) AF: 0.0224 AC: 342 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3470

East Asian (EAS) AF: 0.00579 AC: 30 AN: 5184

South Asian (SAS) AF: 0.138 AC: 664 AN: 4820

European-Finnish (FIN) AF: 0.0215 AC: 228 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 731 AN: 68010

Other (OTH) AF: 0.0384 AC: 81 AN: 2112

Alfa AF: 0.00766 Hom.: 3

Bravo AF: 0.0507

Asia WGS AF: 0.108 AC: 375 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.21
DANN	Benign	0.30
PhyloP100		-0.67
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: rs7571586; hg19: chr2-202139938;