rs17860422

Variant names:

• chr2-201271549-C-T
• rs17860422
• NM_001372051.1:c.339C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080125.2(CASP8):​c.516C>T​(p.Ser172Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,608,458 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (26 hom.)
• Consequence: CASP8 NM_001080125.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.689
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-201271549-C-T is Benign according to our data. Variant chr2-201271549-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.689 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0031 (473/152356) while in subpopulation NFE AF = 0.00472 (321/68040). AF 95% confidence interval is 0.00429. There are 1 homozygotes in GnomAd4. There are 239 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080125.2. 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.339C>T	p.Ser113Ser	synonymous	Exon 3 of 9	NP_001358980.1
	CASP8	NM_001080125.2		c.516C>T	p.Ser172Ser	synonymous	Exon 3 of 9	NP_001073594.1
	CASP8	NM_001400642.1		c.516C>T	p.Ser172Ser	synonymous	Exon 3 of 8	NP_001387571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000673742.1	MANE Select	c.339C>T	p.Ser113Ser	synonymous	Exon 3 of 9	ENSP00000501268.1
	CASP8	ENST00000358485.8	TSL:1	c.516C>T	p.Ser172Ser	synonymous	Exon 3 of 9	ENSP00000351273.4
	CASP8	ENST00000264275.9	TSL:1	c.435C>T	p.Ser145Ser	synonymous	Exon 5 of 10	ENSP00000264275.5

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 474 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00347 AC: 872 AN: 251394 AF XY: 0.00356

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00475

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00379 AC: 5514 AN: 1456102 Hom.: 26 Cov.: 28 AF XY: 0.00380 AC XY: 2753 AN XY: 724764

African (AFR) AF: 0.000779 AC: 26 AN: 33364

American (AMR) AF: 0.00387 AC: 173 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00252 AC: 217 AN: 86138

European-Finnish (FIN) AF: 0.00247 AC: 132 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5760

European-Non Finnish (NFE) AF: 0.00425 AC: 4709 AN: 1106724

Other (OTH) AF: 0.00330 AC: 199 AN: 60226

GnomAD4 genome AF: 0.00310 AC: 473 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74504

African (AFR) AF: 0.000601 AC: 25 AN: 41590

American (AMR) AF: 0.00438 AC: 67 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00472 AC: 321 AN: 68040

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00382 Hom.: 1

Bravo AF: 0.00325

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00578

EpiControl AF: 0.00599

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autoimmune lymphoproliferative syndrome type 2B (2)
-	-	2	not provided (2)
-	-	1	Lung cancer;C0346153:Familial cancer of breast;C1846545:Autoimmune lymphoproliferative syndrome type 2B;C2239176:Hepatocellular carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.44
PhyloP100		-0.69
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs17860422; hg19: chr2-202136272;