rs2241827

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000495723.1(ENSG00000258461):n.*1943T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,596,904 control chromosomes in the GnomAD database, including 398,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.76 ( 44598 hom., cov: 32)

Exomes 𝑓: 0.70 ( 353734 hom. )

Consequence

ENSG00000258461
ENST00000495723.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: -2.08

Publications

7 publications found

Variant links:

Genes affected

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 15-42402746-T-C is Benign according to our data. Variant chr15-42402746-T-C is described in ClinVar as Benign. ClinVar VariationId is 92406.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.1537-48T>C	intron_variant	Intron 12 of 23	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.1537-48T>C	intron_variant	Intron 12 of 22		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.1393-48T>C	intron_variant	Intron 11 of 20		NP_775110.1	P20807-2
CAPN3	NM_173088.2 link	c.1-48T>C	intron_variant	Intron 1 of 12		NP_775111.1	P20807-4A0A0S2Z3E1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000258461	ENST00000495723.1 link	n.*1943T>C	non_coding_transcript_exon_variant	Exon 16 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*1943T>C	3_prime_UTR_variant	Exon 16 of 26	2		ENSP00000492063.1	A0A1W2PQD3
CAPN3	ENST00000397163.8 link	c.1537-48T>C	intron_variant	Intron 12 of 23	1	NM_000070.3	ENSP00000380349.3	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.755

AC:

114785

AN:

151966

Hom.:

44544

Cov.:

show subpopulations

Gnomad AFR

AF:

0.934

Gnomad AMI

AF:

0.785

Gnomad AMR

AF:

0.705

Gnomad ASJ

AF:

0.773

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.696

Gnomad FIN

AF:

0.645

Gnomad MID

AF:

0.744

Gnomad NFE

AF:

0.703

Gnomad OTH

AF:

0.757

GnomAD2 exomes

AF:

0.682

AC:

168544

AN:

247040

AF XY:

0.687

show subpopulations

Gnomad AFR exome

AF:

0.935

Gnomad AMR exome

AF:

0.608

Gnomad ASJ exome

AF:

0.765

Gnomad EAS exome

AF:

0.423

Gnomad FIN exome

AF:

0.633

Gnomad NFE exome

AF:

0.706

Gnomad OTH exome

AF:

0.700

GnomAD4 exome

AF:

0.696

AC:

1006273

AN:

1444820

Hom.:

353734

Cov.:

AF XY:

0.697

AC XY:

502013

AN XY:

719856

show subpopulations

African (AFR)

AF:

0.943

AC:

31266

AN:

33150

American (AMR)

AF:

0.625

AC:

27763

AN:

44456

Ashkenazi Jewish (ASJ)

AF:

0.767

AC:

19965

AN:

26030

East Asian (EAS)

AF:

0.413

AC:

16336

AN:

39538

South Asian (SAS)

AF:

0.707

AC:

60690

AN:

85846

European-Finnish (FIN)

AF:

0.633

AC:

33413

AN:

52766

Middle Eastern (MID)

AF:

0.778

AC:

4303

AN:

5530

European-Non Finnish (NFE)

AF:

0.702

AC:

770160

AN:

1097788

Other (OTH)

AF:

0.710

AC:

42377

AN:

59716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

17743

35485

53228

70970

88713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19334

38668

58002

77336

96670

<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

AF:

0.755

AC:

114895

AN:

152084

Hom.:

44598

Cov.:

AF XY:

0.750

AC XY:

55712

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.935

AC:

38786

AN:

41504

American (AMR)

AF:

0.704

AC:

10756

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.773

AC:

2685

AN:

3472

East Asian (EAS)

AF:

0.428

AC:

2213

AN:

5168

South Asian (SAS)

AF:

0.696

AC:

3350

AN:

4810

European-Finnish (FIN)

AF:

0.645

AC:

6818

AN:

10578

Middle Eastern (MID)

AF:

0.748

AC:

220

AN:

294

European-Non Finnish (NFE)

AF:

0.703

AC:

47766

AN:

67964

Other (OTH)

AF:

0.751

AC:

1587

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1357

2713

4070

5426

6783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.728

Hom.:

56891

Bravo

AF:

0.766

Asia WGS

AF:

0.567

AC:

1972

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 24, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Mar 14, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000070.3: c.1537-48T>C variant in CAPN3 is an intronic variant. The filtering allele frequency for this variant is 0.9344 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 31266/33150 African/African American exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold ≥0.003 for BA1 (BA1). The SpliceAI prediction of 0.00 indicates no splicing impact and does not exceed the LGMD VCEP threshold of ≤0.05 (BP4). This variant is also not in a splice region (BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/14/2025): BA1, BP4, BP7. -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.50

(source)

DANN

Benign

0.34

PhyloP100

-2.1

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=15/85

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over