rs17860405

Variant names:

• chr2-201209484-A-G
• rs17860405
• NM_032977.4:c.1337A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032977.4(CASP10):​c.1337A>G​(p.Tyr446Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,613,824 control chromosomes in the GnomAD database, including 1,305 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (80 hom., cov: 31)
  • Exomes 𝑓: 0.037 (1225 hom.)
• Consequence: CASP10 NM_032977.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.111
• Publications: 28 publications found

Genes affected

CASP10 (HGNC:1500): (caspase 10) This gene encodes a protein which is 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 which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 3 and 7, and the protein itself is processed by caspase 8. Mutations in this gene are associated with type IIA autoimmune lymphoproliferative syndrome, non-Hodgkin lymphoma and gastric cancer. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

CASP10 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2A

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032116473).
• BP6: Variant 2-201209484-A-G is Benign according to our data. Variant chr2-201209484-A-G is described in ClinVar as Benign. ClinVar VariationId is 21728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0282 (4295/152284) while in subpopulation NFE AF = 0.0405 (2758/68018). AF 95% confidence interval is 0.0393. There are 80 homozygotes in GnomAd4. There are 2096 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4295 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP10	NM_032977.4	c.1337A>G	p.Tyr446Cys	missense_variant	Exon 9 of 10	ENST00000286186.11	NP_116759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000286186.11	c.1337A>G	p.Tyr446Cys	missense_variant	Exon 9 of 10	1	NM_032977.4	ENSP00000286186.6

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4295 AN: 152166 Hom.: 80 Cov.: 31

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0296 AC: 7429 AN: 250904 AF XY: 0.0288

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0651

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0371 AC: 54164 AN: 1461540 Hom.: 1225 Cov.: 35 AF XY: 0.0364 AC XY: 26450 AN XY: 727072

African (AFR) AF: 0.00589 AC: 197 AN: 33448

American (AMR) AF: 0.0197 AC: 880 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 332 AN: 26106

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00820 AC: 707 AN: 86230

European-Finnish (FIN) AF: 0.0662 AC: 3538 AN: 53416

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5762

European-Non Finnish (NFE) AF: 0.0419 AC: 46578 AN: 1111836

Other (OTH) AF: 0.0306 AC: 1846 AN: 60378

GnomAD4 genome AF: 0.0282 AC: 4295 AN: 152284 Hom.: 80 Cov.: 31 AF XY: 0.0282 AC XY: 2096 AN XY: 74456

African (AFR) AF: 0.00647 AC: 269 AN: 41572

American (AMR) AF: 0.0254 AC: 388 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00602 AC: 29 AN: 4818

European-Finnish (FIN) AF: 0.0632 AC: 670 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0405 AC: 2758 AN: 68018

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0371 Hom.: 198

Bravo AF: 0.0245

TwinsUK AF: 0.0413 AC: 153

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0374 AC: 322

ExAC AF: 0.0294 AC: 3574

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0367

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2A Benign:2 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 24, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31309545, 16537120, 26323380, 16446975, 17999750)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.6
DANN	Benign	0.67
DEOGEN2	Benign	0.0	.;T;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.73
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0032	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.;.;.
PhyloP100		0.11
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T
Vest4		0.061
ClinPred		0.050	T
GERP RS		1.0
Varity_R		0.25
gMVP		0.81
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: rs17860405; hg19: chr2-202074207;