2-201185954-A-G

Variant names:

• chr2-201185954-A-G
• rs3900115
• NM_032977.4:c.177A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032977.4(CASP10):​c.177A>G​(p.Ser59Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,613,588 control chromosomes in the GnomAD database, including 203,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18041 hom., cov: 31)
  • Exomes 𝑓: 0.50 (185337 hom.)
• Consequence: CASP10 NM_032977.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.715
• Publications: 40 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-201185954-A-G is Benign according to our data. Variant chr2-201185954-A-G is described in ClinVar as Benign. ClinVar VariationId is 333418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.715 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032977.4. 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
	CASP10	NM_032977.4	MANE Select	c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 10	NP_116759.2
	CASP10	NM_032974.5		c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 10	NP_116756.2
	CASP10	NM_001230.5		c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 8	NP_001221.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP10	ENST00000286186.11	TSL:1 MANE Select	c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 10	ENSP00000286186.6
	CASP10	ENST00000448480.1	TSL:1	c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 8	ENSP00000396835.1
	CASP10	ENST00000313728.12	TSL:1	c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 8	ENSP00000314599.7

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73309 AN: 151912 Hom.: 18023 Cov.: 31

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.448 AC: 112498 AN: 250972 AF XY: 0.448

Gnomad AFR exome AF: 0.483

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.515

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.498 AC: 727762 AN: 1461558 Hom.: 185337 Cov.: 48 AF XY: 0.494 AC XY: 359307 AN XY: 727076

African (AFR) AF: 0.486 AC: 16265 AN: 33474

American (AMR) AF: 0.360 AC: 16091 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13649 AN: 26136

East Asian (EAS) AF: 0.197 AC: 7821 AN: 39700

South Asian (SAS) AF: 0.355 AC: 30575 AN: 86248

European-Finnish (FIN) AF: 0.499 AC: 26658 AN: 53396

Middle Eastern (MID) AF: 0.410 AC: 2346 AN: 5728

European-Non Finnish (NFE) AF: 0.526 AC: 585201 AN: 1111786

Other (OTH) AF: 0.483 AC: 29156 AN: 60384

GnomAD4 genome AF: 0.483 AC: 73370 AN: 152030 Hom.: 18041 Cov.: 31 AF XY: 0.476 AC XY: 35338 AN XY: 74314

African (AFR) AF: 0.484 AC: 20057 AN: 41452

American (AMR) AF: 0.417 AC: 6379 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1822 AN: 3464

East Asian (EAS) AF: 0.222 AC: 1150 AN: 5180

South Asian (SAS) AF: 0.334 AC: 1605 AN: 4810

European-Finnish (FIN) AF: 0.511 AC: 5397 AN: 10558

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35471 AN: 67968

Other (OTH) AF: 0.472 AC: 994 AN: 2108

Alfa AF: 0.504 Hom.: 60411

Bravo AF: 0.474

Asia WGS AF: 0.301 AC: 1048 AN: 3478

EpiCase AF: 0.506

EpiControl AF: 0.516

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported.

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Autoimmune lymphoproliferative syndrome type 2A Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Benign:2 Other:1

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

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.78
DANN	Benign	0.50
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3900115; hg19: chr2-202050677; COSMIC: COSV53776970; COSMIC: COSV53776970;