rs1555423046

Positions:

• chr15-42409944-GAC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.2069_2070delAC​(p.His690fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000479 in 1,460,286 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CAPN3 NM_000070.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.02

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-42409944-GAC-G is Pathogenic according to our data. Variant chr15-42409944-GAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 551927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42409944-GAC-G is described in Lovd as [Pathogenic]. Variant chr15-42409944-GAC-G is described in Lovd as [Pathogenic]. Variant chr15-42409944-GAC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2069_2070delAC	p.His690fs	frameshift_variant	19/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2069_2070delAC	p.His690fs	frameshift_variant	19/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.74_75delAC	p.His25fs	frameshift_variant	6/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.74_75delAC	p.His25fs	frameshift_variant	6/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.74_75delAC	p.His25fs	frameshift_variant	7/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.74_75delAC	p.His25fs	frameshift_variant	6/11			ENSP00000501112.1
CAPN3	ENST00000673743	c.-29_-28delAC		5_prime_UTR_variant	6/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2505_*2506delAC		non_coding_transcript_exon_variant	21/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2505_*2506delAC		3_prime_UTR_variant	21/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251412 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460286 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726386

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: 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

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2023	This sequence change creates a premature translational stop signal (p.His690Argfs*9) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individual(s) with inherited muscular disorders, including autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 21204801, 27363342). ClinVar contains an entry for this variant (Variation ID: 551927). For these reasons, this variant has been classified as Pathogenic. -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1555423046; hg19: chr15-42702142;