Genetic Variant NM_032977.4:c.81T>G (chr2-201185858-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032977.4(CASP10):c.81T>G(p.Ile27Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I27I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CASP10
NM_032977.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.41

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autoimmune lymphoproliferative syndrome type 2A
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
autoimmune lymphoproliferative syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CASP10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP10	NM_032977.4	MANE Select	c.81T>G	p.Ile27Met	missense	Exon 2 of 10	NP_116759.2
CASP10	NM_032974.5		c.81T>G	p.Ile27Met	missense	Exon 2 of 10	NP_116756.2
CASP10	NM_001230.5		c.81T>G	p.Ile27Met	missense	Exon 2 of 8	NP_001221.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP10	ENST00000286186.11	TSL:1 MANE Select	c.81T>G	p.Ile27Met	missense	Exon 2 of 10	ENSP00000286186.6	Q92851-4
CASP10	ENST00000448480.1	TSL:1	c.81T>G	p.Ile27Met	missense	Exon 2 of 8	ENSP00000396835.1	Q92851-5
CASP10	ENST00000313728.12	TSL:1	c.81T>G	p.Ile27Met	missense	Exon 2 of 8	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.036

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.3

PhyloP100

-1.4

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.59

MutPred

0.84

Loss of ubiquitination at K23 (P = 0.0992)

MVP

0.97

MPC

0.43

ClinPred

0.96

GERP RS

-2.9

Varity_R

0.79

gMVP

0.47

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over