chr2-201287058-T-C

Variant names:

• chr2-201287058-T-C
• rs1045494
• NM_001372051.1:c.*464T>C

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.*464T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 188,986 control chromosomes in the GnomAD database, including 1,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1347 hom., cov: 32)
  • Exomes 𝑓: 0.094 (315 hom.)
• Consequence: CASP8 NM_001372051.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.37
• Publications: 20 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-201287058-T-C is Benign according to our data. Variant chr2-201287058-T-C is described in ClinVar as Benign. ClinVar VariationId is 333520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.252 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	NM_001372051.1	MANE Select	c.*464T>C		3_prime_UTR	Exon 9 of 9	NP_001358980.1	Q14790-1
	CASP8	NM_001080125.2		c.*464T>C		3_prime_UTR	Exon 9 of 9	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.*464T>C		3_prime_UTR	Exon 8 of 8	NP_001387571.1	A0A8Q3SID9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000673742.1	MANE Select	c.*464T>C		3_prime_UTR	Exon 9 of 9	ENSP00000501268.1	Q14790-1
	CASP8	ENST00000358485.8	TSL:1	c.*464T>C		3_prime_UTR	Exon 9 of 9	ENSP00000351273.4	Q14790-9
	CASP8	ENST00000323492.11	TSL:1	c.*464T>C		3_prime_UTR	Exon 8 of 8	ENSP00000325722.7	Q14790-2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15836 AN: 152176 Hom.: 1339 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.0936 AC: 3433 AN: 36692 Hom.: 315 Cov.: 0 AF XY: 0.108 AC XY: 2053 AN XY: 19088

African (AFR) AF: 0.206 AC: 106 AN: 514

American (AMR) AF: 0.0307 AC: 99 AN: 3226

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 67 AN: 616

East Asian (EAS) AF: 0.201 AC: 393 AN: 1958

South Asian (SAS) AF: 0.252 AC: 1316 AN: 5220

European-Finnish (FIN) AF: 0.0423 AC: 72 AN: 1704

Middle Eastern (MID) AF: 0.191 AC: 324 AN: 1694

European-Non Finnish (NFE) AF: 0.0450 AC: 890 AN: 19796

Other (OTH) AF: 0.0845 AC: 166 AN: 1964

GnomAD4 genome AF: 0.104 AC: 15876 AN: 152294 Hom.: 1347 Cov.: 32 AF XY: 0.107 AC XY: 7996 AN XY: 74470

African (AFR) AF: 0.210 AC: 8703 AN: 41536

American (AMR) AF: 0.0492 AC: 753 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 284 AN: 3468

East Asian (EAS) AF: 0.202 AC: 1051 AN: 5192

South Asian (SAS) AF: 0.265 AC: 1276 AN: 4824

European-Finnish (FIN) AF: 0.0389 AC: 413 AN: 10618

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3074 AN: 68042

Other (OTH) AF: 0.101 AC: 214 AN: 2116

Alfa AF: 0.0666 Hom.: 1850

Bravo AF: 0.107

Asia WGS AF: 0.230 AC: 798 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autoimmune lymphoproliferative syndrome type 2B (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.3
DANN	Benign	0.30
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs1045494; hg19: chr2-202151781; COSMIC: COSV104376363; COSMIC: COSV104376363;