rs1555421263

Variant names:

• chr15-42394255-G-A
• rs1555421263
• NM_000070.3:c.1030-1G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-42394255-G-A
• chr15-42394255-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.1030-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000712 in 1,403,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CAPN3 NM_000070.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.84
• Publications: 1 publications found

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

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.2, offset of 1, new splice context is: ctctttctgtgtgcttaaAGtcc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-42394255-G-A is Pathogenic according to our data. Variant chr15-42394255-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1030-1G>A		splice_acceptor_variant, intron_variant	Intron 7 of 23	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1030-1G>A		splice_acceptor_variant, intron_variant	Intron 7 of 22		NP_077320.1
CAPN3	NM_173087.2	c.886-1G>A		splice_acceptor_variant, intron_variant	Intron 6 of 20		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1030-1G>A		splice_acceptor_variant, intron_variant	Intron 7 of 23	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*826-1G>A		splice_acceptor_variant, intron_variant	Intron 11 of 25	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403510 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 692626

African (AFR) AF: 0.00 AC: 0 AN: 31908

American (AMR) AF: 0.00 AC: 0 AN: 36132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25210

East Asian (EAS) AF: 0.00 AC: 0 AN: 36226

South Asian (SAS) AF: 0.00 AC: 0 AN: 79476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081036

Other (OTH) AF: 0.00 AC: 0 AN: 58200

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3

Dec 03, 2018

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.1030-1G>A variant in CAPN3 was identified by our study in the compound heterozygous state with a pathogenic variant in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with LGMD and increases the likelihood that the p.Thr184ArgfsTer36 variant is pathogenic. The c.1030-1G>A variant in CAPN3 was reported in at least 1 individual in the literature (PMID: 18854869, 20635405), and was absent from large population studies. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to a frameshift and an abnormal or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive LGMD. RNA and protein analyses of a muscle biopsy from an individual compound heterozygous with this variant and a pathogenic variant provide some evidence that the c.1030-1G>A variant may impact splicing and eliminate translation (PMID: 20635405). This variant has also been reported likely pathogenic in ClinVar (Variation ID: 556764). In summary, although additional studies are required to fully establish its clinical significance, the c.1030-1G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PVS1_moderate, PM3_Supporting (Richards 2015). -

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 7 of the CAPN3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 18854869). ClinVar contains an entry for this variant (Variation ID: 556764). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 23, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.98
Eigen	Pathogenic	0.88
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.8
GERP RS		5.4
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
Splicevardb		3.0
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 2
DS_AL_spliceai		0.80		Position offset: 1

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

Other links and lift over

dbSNP: rs1555421263; hg19: chr15-42686453;