Variant 2-240586953-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_023083.4(CAPN10):c.42C>G(p.Phe14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000226 in 1,326,522 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

CAPN10
NM_023083.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN10	NM_023083.4 linkuse as main transcript	c.42C>G	p.Phe14Leu	missense_variant	1/12	ENST00000391984.7	NP_075571.2
CAPN10	NM_023085.4 linkuse as main transcript	c.42C>G	p.Phe14Leu	missense_variant	1/10		NP_075573.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN10	ENST00000391984.7 linkuse as main transcript	c.42C>G	p.Phe14Leu	missense_variant	1/12	1	NM_023083.4	ENSP00000375844	P1	Q9HC96-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000226

AC:

AN:

1326522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

653548

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:

0.00000286

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.42C>G (p.F14L) alteration is located in exon 1 (coding exon 1) of the CAPN10 gene. This alteration results from a C to G substitution at nucleotide position 42, causing the phenylalanine (F) at amino acid position 14 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;.;.;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.73

D;D;D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

4.1

H;.;H;H;H

MutationTaster

Benign

0.99

D;D;D;D;D;N

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-4.0

D;D;D;N;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0050

D;D;D;T;D

Sift4G

Uncertain

0.0090

D;D;D;T;D

Polyphen

0.99

D;.;D;D;D

Vest4

0.54

MutPred

0.86

Gain of MoRF binding (P = 0.1319);Gain of MoRF binding (P = 0.1319);Gain of MoRF binding (P = 0.1319);Gain of MoRF binding (P = 0.1319);Gain of MoRF binding (P = 0.1319);

MVP

0.83

MPC

1.2

ClinPred

1.0

GERP RS

2.4

Varity_R

0.89

gMVP

0.75

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over