chr2-201257992-T-G

Variant names:

• chr2-201257992-T-G
• rs17860418
• ENST00000264275.9:c.-26-8469T>G

Variant summary

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

The NM_001228.5(CASP8):​c.-26-8469T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 507,786 control chromosomes in the GnomAD database, including 1,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (320 hom., cov: 32)
  • Exomes 𝑓: 0.044 (751 hom.)
• Consequence: CASP8 NM_001228.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.121
• Publications: 5 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=-0.79).
• BP6: Variant 2-201257992-T-G is Benign according to our data. Variant chr2-201257992-T-G is described in ClinVar as Benign. ClinVar VariationId is 1263107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001228.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	NM_001228.5		c.-26-8469T>G		intron	N/A	NP_001219.2
	CASP8	NM_001400648.1		c.-26-8469T>G		intron	N/A	NP_001387577.1	Q14790-1
	CASP8	NM_001400651.1		c.-26-8469T>G		intron	N/A	NP_001387580.1	Q14790-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000264275.9	TSL:1	c.-26-8469T>G		intron	N/A	ENSP00000264275.5	Q14790-4
	CASP8	ENST00000392258.7	TSL:1	c.-26-8469T>G		intron	N/A	ENSP00000376087.3	Q14790-5
	CASP8	ENST00000471383.5	TSL:1	n.251-8469T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 7926 AN: 152146 Hom.: 322 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0459

GnomAD4 exome AF: 0.0439 AC: 15615 AN: 355522 Hom.: 751 Cov.: 3 AF XY: 0.0511 AC XY: 9688 AN XY: 189568

African (AFR) AF: 0.106 AC: 1095 AN: 10352

American (AMR) AF: 0.0233 AC: 365 AN: 15636

Ashkenazi Jewish (ASJ) AF: 0.0376 AC: 407 AN: 10816

East Asian (EAS) AF: 0.00308 AC: 67 AN: 21760

South Asian (SAS) AF: 0.146 AC: 6431 AN: 43930

European-Finnish (FIN) AF: 0.0414 AC: 790 AN: 19078

Middle Eastern (MID) AF: 0.0261 AC: 40 AN: 1532

European-Non Finnish (NFE) AF: 0.0267 AC: 5674 AN: 212182

Other (OTH) AF: 0.0369 AC: 746 AN: 20236

GnomAD4 genome AF: 0.0521 AC: 7934 AN: 152264 Hom.: 320 Cov.: 32 AF XY: 0.0528 AC XY: 3930 AN XY: 74458

African (AFR) AF: 0.103 AC: 4299 AN: 41544

American (AMR) AF: 0.0269 AC: 412 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3470

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5188

South Asian (SAS) AF: 0.146 AC: 702 AN: 4818

European-Finnish (FIN) AF: 0.0387 AC: 411 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0268 AC: 1821 AN: 68020

Other (OTH) AF: 0.0455 AC: 96 AN: 2112

Alfa AF: 0.0329 Hom.: 156

Bravo AF: 0.0508

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.70
PhyloP100		-0.12
PromoterAI		0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17860418; hg19: chr2-202122715;