rs1861269

Variant names:

• chr2-201262215-G-A
• rs1861269
• NM_001372051.1:c.-27+1602G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372051.1(CASP8):​c.-27+1602G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 151,948 control chromosomes in the GnomAD database, including 1,005 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 0.085 (1005 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.586
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372051.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	NM_001372051.1	MANE Select	c.-27+1602G>A		intron	N/A	NP_001358980.1
	CASP8	NM_001080125.2		c.151+3833G>A		intron	N/A	NP_001073594.1
	CASP8	NM_001400642.1		c.151+3833G>A		intron	N/A	NP_001387571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000673742.1	MANE Select	c.-27+1602G>A		intron	N/A	ENSP00000501268.1
	CASP8	ENST00000358485.8	TSL:1	c.151+3833G>A		intron	N/A	ENSP00000351273.4
	CASP8	ENST00000264275.9	TSL:1	c.-26-4246G>A		intron	N/A	ENSP00000264275.5

Frequencies

GnomAD3 genomes AF: 0.0847 AC: 12854 AN: 151830 Hom.: 1005 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0427

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.00578

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0805

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0847 AC: 12867 AN: 151948 Hom.: 1005 Cov.: 32 AF XY: 0.0853 AC XY: 6331 AN XY: 74254

African (AFR) AF: 0.202 AC: 8382 AN: 41402

American (AMR) AF: 0.0426 AC: 651 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 158 AN: 3462

East Asian (EAS) AF: 0.00579 AC: 30 AN: 5180

South Asian (SAS) AF: 0.149 AC: 720 AN: 4822

European-Finnish (FIN) AF: 0.0418 AC: 440 AN: 10516

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0336 AC: 2285 AN: 67990

Other (OTH) AF: 0.0797 AC: 168 AN: 2108

Alfa AF: 0.0656 Hom.: 85

Bravo AF: 0.0876

Asia WGS AF: 0.114 AC: 397 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.5
DANN	Benign	0.76
PhyloP100		0.59
PromoterAI		-0.029	Neutral
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: rs1861269; hg19: chr2-202126938;