2-201209363-A-T

Position:

chr2-201209363-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000286186.11(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. 14/20 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 same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.0034 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0044 ( 35 hom. )

Consequence

CASP10
ENST00000286186.11 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 made for transcript

Verdict is Benign. Variant got -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: {Benign=2, Uncertain_significance=1, Likely_benign=3, not_provided=1}. 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/exons	MANE	Protein	UniProt
CASP10	NM_032977.4 linkuse as main transcript	c.1216A>T	p.Ile406Leu	missense_variant	9/10	ENST00000286186.11	NP_116759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000286186.11 linkuse as main transcript	c.1216A>T	p.Ile406Leu	missense_variant	9/10	1	NM_032977.4	ENSP00000286186	P2	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

GnomAD3 exomes

AF:

0.00453

AC:

1136

AN:

251050

Hom.:

AF XY:

0.00532

AC XY:

722

AN XY:

135704

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 SAS exome

AF:

0.0146

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

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00187

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0150

Gnomad4 FIN exome

AF:

0.00489

Gnomad4 NFE exome

AF:

0.00404

Gnomad4 OTH exome

AF:

0.00386

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

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0139

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.00523

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00422

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

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CASP10: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2022	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) -

Autoimmune lymphoproliferative syndrome type 2A

Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

Hypomyelination and Congenital Cataract

Benign:1

Benign, criteria provided, single submitter

research

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

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;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;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

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