15-42410926-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000070.3(CAPN3):c.2306G>T(p.Arg769Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R769P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 10.0

Publications

0 publications found

Variant links:

Genes affected

CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

CAPN3 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
muscular dystrophy, limb-girdle, autosomal dominant 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
muscular dystrophy, limb-girdle, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000070.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42410926-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 652571.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 15-42410926-G-T is Pathogenic according to our data. Variant chr15-42410926-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2578458.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2306G>T	p.Arg769Leu	missense_variant	Exon 22 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CAPN3	ENST00000397163.8 link	c.2306G>T	p.Arg769Leu	missense_variant	Exon 22 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1 link	c.311G>T	p.Arg104Leu	missense_variant	Exon 9 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1 link	c.311G>T	p.Arg104Leu	missense_variant	Exon 9 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1 link	c.311G>T	p.Arg104Leu	missense_variant	Exon 10 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1 link	c.311G>T	p.Arg104Leu	missense_variant	Exon 9 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1 link	c.209G>T	p.Arg70Leu	missense_variant	Exon 9 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1 link	n.*2742G>T		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1 link	n.*2742G>T		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Uncertain:1

Institute of Human Genetics, University of Wuerzburg

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.;D;.;.;.;.;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;.;D;.;D;.

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

.;.;.;H;.;.;.;.;.;.;.

PhyloP100

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.2

.;D;D;D;D;D;D;.;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

.;D;D;D;D;D;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;T;T;T;T;T

Polyphen

1.0

.;D;D;D;.;.;.;.;.;.;.

Vest4

0.98

MutPred

0.93

.;.;.;Loss of catalytic residue at R769 (P = 0.0772);.;.;.;.;.;.;.;

MVP

0.99

MPC

0.70

ClinPred

1.0

GERP RS

5.4

Varity_R

0.94

gMVP

0.93

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over