Genetic Variant NM_032977.4:c.478G>C (chr2-201193020-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032977.4(CASP10):c.478G>C(p.Gly160Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G160S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CASP10
NM_032977.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.930

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), 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15744558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP10	NM_032977.4 link	c.478G>C	p.Gly160Arg	missense_variant	Exon 4 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.478G>C	p.Gly160Arg	missense_variant	Exon 4 of 10	1	NM_032977.4	ENSP00000286186.6		Q92851-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251246

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461406

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111678

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Uncertain

0.45

.;.;T;.;.;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.71

T;T;T;T;T;T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.16

T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

L;L;L;L;L;L;L

PhyloP100

0.93

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D;D

REVEL

Benign

0.062

Sift

Benign

0.16

T;T;T;T;T;T;T

Sift4G

Benign

0.37

T;T;T;T;T;T;T

Polyphen

0.021

B;.;B;.;P;P;P

Vest4

0.14

MutPred

0.57

Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

0.62

MPC

0.097

ClinPred

0.23

GERP RS

0.88

Varity_R

0.23

gMVP

0.25

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over