rs374665929

Positions:

chr15-42399483-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000070.3(CAPN3):c.1194-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,611,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 intron

Scores

Splicing: ADA: 0.9900

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: -0.0700

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 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 15-42399483-A-G is Pathogenic according to our data. Variant chr15-42399483-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 217146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399483-A-G is described in Lovd as [Pathogenic]. Variant chr15-42399483-A-G is described in Lovd as [Pathogenic]. Variant chr15-42399483-A-G is described in Lovd as [Likely_pathogenic]. Variant chr15-42399483-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.1194-9A>G	intron_variant	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.1194-9A>G	intron_variant		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.1050-9A>G	intron_variant		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8 link	c.1194-9A>G		intron_variant		1	NM_000070.3	ENSP00000380349.3		P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*990-9A>G		intron_variant		2		ENSP00000492063.1		A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251462

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135904

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1459346

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151774

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74106

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000961

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 22, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2023	Published functional studies demonstrate a damaging effect by impairing splicing causing at least a partial intron 9 retention (Salem et al., 2012); This variant is associated with the following publications: (PMID: 25525159, 10330340, 22158424, 33335567, 34720847, 32528171, 31788660, 25135358, 27500519, 30919934, 28403181, 11525884, 26404900) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This sequence change falls in intron 9 of the CAPN3 gene. It does not directly change the encoded amino acid sequence of the CAPN3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs374665929, gnomAD 0.007%). This variant has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 11525884, 12461690, 18055493, 22158424, 25135358). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217146). Studies have shown that this variant results in the retention of 8 nucleotides of intron 9 and introduces a premature termination codon (PMID: 22158424). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 11, 2017	- -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3+PM3_Strong+PP1_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2024	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 19, 2024

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The heterozygous c.1194-9A>G variant in CAPN3 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 17622), in one individual with limb-girdle muscular dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 17622), however the phase of these variants are unknown at this time. The c.1194-9A>G variant in CAPN3 has been previously reported in twelve individuals with autosomal recessive limb-girdle muscular dystrophy 1 (PMID: 25135358, PMID: 27066573, PMID: 10330340, PMID: 10330340, PMID: 31788660, PMID: 32528171, PMID: 30919934, PMID: 34720847, PMID: 33335567, PMID: 18055493, PMID: 11525884, PMID: 22158424, PMID: 12461690), segregated with disease in 3 affected relatives from one family (PMID: 22158424), but has been identified in 0.006% (1/16256) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374665929). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 217146) and has been interpreted as pathogenic by PerkinElmer Genomics, Natera, Inc, Athena Diagnostics, Invitae, and Eurofins NTD LLC, and as likely pathogenic by Counsyl and GeneDx. Of these twelve affected individuals previously reported (PMID: 25135358, PMID: 27066573, PMID: 10330340, PMID: 10330340, PMID: 31788660, PMID: 32528171, PMID: 30919934, PMID: 34720847, PMID: 33335567, PMID: 18055493, PMID: 11525884, PMID: 22158424, PMID: 12461690), 6 were homozygotes (PMID: 10330340, PMID: 30919934, PMID: 22158424, PMID: 12461690, PMID: 11525884, PMID: 30919934) , two were compound heterozygotes who carried pathogenic variants in trans (PMID: 25135358, PMID: 31788660), one was a compound heterozygote who carried a likely pathogenic variant in unknown phase (PMID: 18055493), and four were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 25135358, PMID: 27066573, PMID: 34720847), and, in addition, the individual identified by our study was a compound heterozygote who carried a pathogenic variant (ClinVar Variation ID: 17622) in unknown phase, which increases the likelihood that the c.1194-9A>G variant is pathogenic. RT-PCR analysis performed on RNA from an affected individual‚Äôs muscle biopsy showed altered splicing, with incorporation of eight nucleotides from intron 9 in a transcript lacking the seven first exons, versus the wild-type transcript seen in RNA from a muscle biopsy of a unaffected control individual (PMID: 22158424). This variant is located in the 3‚Äô splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb-girdle muscular dystrophy 1. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP1 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

1.0

Position offset: 1

DS_AL_spliceai

0.97

Position offset: 9

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over