rs1861270

Variant names:

• chr2-201261892-A-G
• rs1861270
• NM_001372051.1:c.-27+1279A>G

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+1279A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 152,020 control chromosomes in the GnomAD database, including 41,088 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 0.73 (41085 hom., cov: 31)
  • Exomes 𝑓: 0.88 (3 hom.)
• Consequence: CASP8 NM_001372051.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.291
• Publications: 16 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.-27+1279A>G		intron_variant	Intron 1 of 8	ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.-27+1279A>G		intron_variant	Intron 1 of 8		NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111198 AN: 151894 Hom.: 41046 Cov.: 31

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.688

GnomAD4 exome AF: 0.875 AC: 7 AN: 8 Hom.: 3 AF XY: 0.833 AC XY: 5 AN XY: 6

African (AFR) AF: 1.00 AC: 2 AN: 2

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) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 3 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.732 AC: 111284 AN: 152012 Hom.: 41085 Cov.: 31 AF XY: 0.729 AC XY: 54102 AN XY: 74264

African (AFR) AF: 0.789 AC: 32713 AN: 41480

American (AMR) AF: 0.583 AC: 8889 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2201 AN: 3472

East Asian (EAS) AF: 0.712 AC: 3681 AN: 5172

South Asian (SAS) AF: 0.831 AC: 4007 AN: 4822

European-Finnish (FIN) AF: 0.686 AC: 7202 AN: 10498

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 50210 AN: 67988

Other (OTH) AF: 0.689 AC: 1456 AN: 2114

Alfa AF: 0.737 Hom.: 17900

Bravo AF: 0.723

Asia WGS AF: 0.799 AC: 2781 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.0
DANN	Benign	0.70
PhyloP100		-0.29
PromoterAI		0.0082	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: rs1861270; hg19: chr2-202126615; COSMIC: COSV51846764;