Genetic Variant NM_023083.4:c.161G>C (chr2-240589362-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_023083.4(CAPN10):c.161G>C(p.Arg54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAPN10
NM_023083.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.765

Variant links:

Genes affected

CAPN10 (HGNC:1477): (calpain 10) Calpains represent a ubiquitous, well-conserved family of calcium-dependent cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large catalytic subunit has four domains: domain I, the N-terminal regulatory domain that is processed upon calpain activation; domain II, the protease domain; domain III, a linker domain of unknown function; and domain IV, the calmodulin-like calcium-binding domain. This gene encodes a large subunit. It is an atypical calpain in that it lacks the calmodulin-like calcium-binding domain and instead has a divergent C-terminal domain. It is similar in organization to calpains 5 and 6. This gene is associated with type 2 or non-insulin-dependent diabetes mellitus (NIDDM), and is located within the NIDDM1 region. Multiple alternative transcript variants have been described for this gene. [provided by RefSeq, Sep 2010]

CAPN10 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN10	NM_023083.4 link	c.161G>C	p.Arg54Pro	missense_variant	Exon 2 of 12	ENST00000391984.7	NP_075571.2	Q9HC96-1
CAPN10	NM_023085.4 link	c.161G>C	p.Arg54Pro	missense_variant	Exon 2 of 10		NP_075573.3	Q9HC96-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN10	ENST00000391984.7 link	c.161G>C	p.Arg54Pro	missense_variant	Exon 2 of 12	1	NM_023083.4	ENSP00000375844.2		Q9HC96-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;.;.;.

Eigen

Benign

-0.0050

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Pathogenic

3.0

M;.;M;M

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Pathogenic

0.69

Sift

Benign

0.057

T;T;D;D

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.97

D;.;D;D

Vest4

0.64

MutPred

0.69

Gain of catalytic residue at P53 (P = 0.0107);Gain of catalytic residue at P53 (P = 0.0107);Gain of catalytic residue at P53 (P = 0.0107);Gain of catalytic residue at P53 (P = 0.0107);

MVP

0.93

MPC

1.2

ClinPred

0.97

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.61

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over