2-201209363-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_032977.4(CASP10):c.1216A>T(p.Ile406Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,614,130 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0034 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0044 ( 35 hom. )

Consequence

CASP10
NM_032977.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: -1.20

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006909907).

BP6

Variant 2-201209363-A-T is Benign according to our data. Variant chr2-201209363-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 333435.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=3, Benign=2}. Variant chr2-201209363-A-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 514 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP10	NM_032977.4 link	c.1216A>T	p.Ile406Leu	missense_variant	Exon 9 of 10	ENST00000286186.11	NP_116759.2	Q92851-4A0A0S2Z3Z5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000286186.11 link	c.1216A>T	p.Ile406Leu	missense_variant	Exon 9 of 10	1	NM_032977.4	ENSP00000286186.6		Q92851-4

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

513

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00523

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00453

AC:

1136

AN:

251050

AF XY:

0.00532

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00494

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00439

AC:

6418

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

3466

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00132

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00187

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0150

AC:

1290

AN:

86258

Gnomad4 FIN exome

AF:

0.00489

AC:

261

AN:

53418

Gnomad4 NFE exome

AF:

0.00404

AC:

4490

AN:

1112012

Gnomad4 Remaining exome

AF:

0.00386

AC:

233

AN:

60394

Heterozygous variant carriers

398

796

1194

1592

1990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00338

AC:

514

AN:

152240

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000409

AC:

0.000409224

AN:

0.000409224

Gnomad4 AMR

AF:

0.00144

AC:

0.00143904

AN:

0.00143904

Gnomad4 ASJ

AF:

0.00144

AC:

0.00144092

AN:

0.00144092

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.0139

AC:

0.0139351

AN:

0.0139351

Gnomad4 FIN

AF:

0.00386

AC:

0.00386209

AN:

0.00386209

Gnomad4 NFE

AF:

0.00523

AC:

0.00523345

AN:

0.00523345

Gnomad4 OTH

AF:

0.00284

AC:

0.00283822

AN:

0.00283822

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00351

Hom.:

Bravo

AF:

0.00232

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00494

AC:

600

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Mar 08, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published in vitro functional studies showed that this variant conferred significant resistance to apoptosis in transfected cells which was even stronger when co-transfected with wild-type CASP10 indicating a probable dominant negative effect (Zhu et al., 2006); This variant is associated with the following publications: (PMID: 22995991, 27535533, 16446975, 32599613, 27378136, 31309545) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CASP10: BP4, BS1, BS2 -

Jan 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoimmune lymphoproliferative syndrome type 2A

Benign:2Other:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Hypomyelination and Congenital Cataract

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Ile406Leu variant in CASP10 has been identified in 2 individuals with autoimmune lymphoproliferative syndrome (PMID: 16446975), but has also been identified in >1% of South Asian chromosomes and 9 homozygotes by ExAC (http://gnomad.broadinstitute.org/). This variant has also been identified in a heterozygous individual and a homozygous individual who have not been reported to have disease (PMID: 22995991). In vitro functional studies provide some evidence that the p.Ile406Leu variant may slightly impact protein function (PMID: 16446975). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal dominant autoimmune lymphoproliferative syndrome. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

2.5

DANN

Benign

0.84

DEOGEN2

Benign

0.034

.;T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.77

T;T;T;T;T

MetaRNN

Benign

0.0069

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.39

N;N;.;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.96

N;N;N;N;N

REVEL

Benign

0.27

Sift

Benign

0.14

T;T;T;T;T

Sift4G

Benign

0.50

T;T;T;T;T

Polyphen

0.20

B;P;P;B;P

Vest4

0.14

MutPred

0.57

Loss of catalytic residue at P408 (P = 0.0354);Loss of catalytic residue at P408 (P = 0.0354);.;.;.;

MVP

0.37

MPC

0.078

ClinPred

0.00074

GERP RS

-0.46

Varity_R

0.12

gMVP

0.23

Mutation Taster

=99/1

polymorphism

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over