rs1555423027

Variant names:

• chr15-42409844-CG-C
• rs1555423027
• NM_000070.3:c.2050+1delG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.2050+1delG variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,164,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CAPN3 NM_000070.3 splice_donor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 28, new splice context is: gggGTgggt. 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 15-42409844-CG-C is Pathogenic according to our data. Variant chr15-42409844-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42409844-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2050+1delG		splice_donor_variant, intron_variant	Intron 18 of 23	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2050+1delG		splice_donor_variant, intron_variant	Intron 18 of 23	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.55+1delG		splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.55+1delG		splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.55+1delG		splice_donor_variant, intron_variant	Intron 6 of 11			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.55+1delG		splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.-43+1delG		splice_donor_variant, intron_variant	Intron 5 of 10			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2486+1delG		splice_donor_variant, intron_variant	Intron 20 of 25	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000344 AC: 4 AN: 1164392 Hom.: 0 Cov.: 37 AF XY: 0.00000516 AC XY: 3 AN XY: 581910

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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:2

Apr 02, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 557598). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with limb girdle muscular dystrophy (PMID: 11525884, 15689361, 26632398, 30107846). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 18 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). -

not provided Pathogenic:1

Jun 27, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -25
DS_DL_spliceai		1.0		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555423027; hg19: chr15-42702042;