chr2-201217736-T-A

Variant names:

• chr2-201217736-T-A
• rs13006529
• NM_032977.4:c.1564T>A

Variant summary

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

The NM_032977.4(CASP10):​c.1564T>A​(p.Leu522Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 1,613,078 control chromosomes in the GnomAD database, including 174,451 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L522T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.42 (13803 hom., cov: 30)
  • Exomes 𝑓: 0.46 (160648 hom.)
• Consequence: CASP10 NM_032977.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.00700
• Publications: 61 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=2.61724E-4).
• BP6: Variant 2-201217736-T-A is Benign according to our data. Variant chr2-201217736-T-A is described in ClinVar as Benign. ClinVar VariationId is 333442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP10	NM_032977.4	c.1564T>A	p.Leu522Ile	missense_variant	Exon 10 of 10	ENST00000286186.11	NP_116759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000286186.11	c.1564T>A	p.Leu522Ile	missense_variant	Exon 10 of 10	1	NM_032977.4	ENSP00000286186.6

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63662 AN: 151712 Hom.: 13805 Cov.: 30

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.408 AC: 102459 AN: 251370 AF XY: 0.408

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.328

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.474

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.462 AC: 675337 AN: 1461248 Hom.: 160648 Cov.: 38 AF XY: 0.457 AC XY: 332582 AN XY: 726962

African (AFR) AF: 0.347 AC: 11611 AN: 33464

American (AMR) AF: 0.339 AC: 15158 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 11424 AN: 26130

East Asian (EAS) AF: 0.192 AC: 7619 AN: 39688

South Asian (SAS) AF: 0.290 AC: 24990 AN: 86252

European-Finnish (FIN) AF: 0.473 AC: 25263 AN: 53386

Middle Eastern (MID) AF: 0.367 AC: 2117 AN: 5762

European-Non Finnish (NFE) AF: 0.495 AC: 550575 AN: 1111482

Other (OTH) AF: 0.440 AC: 26580 AN: 60368

GnomAD4 genome AF: 0.419 AC: 63667 AN: 151830 Hom.: 13803 Cov.: 30 AF XY: 0.414 AC XY: 30675 AN XY: 74172

African (AFR) AF: 0.349 AC: 14433 AN: 41388

American (AMR) AF: 0.388 AC: 5924 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1511 AN: 3468

East Asian (EAS) AF: 0.212 AC: 1092 AN: 5160

South Asian (SAS) AF: 0.270 AC: 1302 AN: 4816

European-Finnish (FIN) AF: 0.484 AC: 5096 AN: 10520

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.485 AC: 32940 AN: 67900

Other (OTH) AF: 0.427 AC: 902 AN: 2110

Alfa AF: 0.468 Hom.: 5544

Bravo AF: 0.412

TwinsUK AF: 0.498 AC: 1847

ALSPAC AF: 0.511 AC: 1968

ESP6500AA AF: 0.351 AC: 1547

ESP6500EA AF: 0.490 AC: 4211

ExAC AF: 0.410 AC: 49761

Asia WGS AF: 0.230 AC: 803 AN: 3478

EpiCase AF: 0.470

EpiControl AF: 0.481

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 63% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autoimmune lymphoproliferative syndrome type 2A Benign:3

Jan 13, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.95
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.49	T;T;T
MetaRNN	Benign	0.00026	T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		0.0070
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.18	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.36	B;B;B
Vest4		0.064
MPC		0.44
ClinPred		0.0096	T
GERP RS		-1.4
gMVP		0.21
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: rs13006529; hg19: chr2-202082459; COSMIC: COSV53781246; COSMIC: COSV53781246;