rs1555423426

Positions:

• chr15-42411737-CTTCT-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000070.3(CAPN3):​c.2440-6_2440-3delTTTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 26)
• Consequence: CAPN3 NM_000070.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 2.59

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-42411737-CTTCT-C is Pathogenic according to our data. Variant chr15-42411737-CTTCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550740.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr15-42411737-CTTCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2440-6_2440-3delTTTC		splice_region_variant, intron_variant		ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2440-6_2440-3delTTTC		splice_region_variant, intron_variant		1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.445-6_445-3delTTTC		splice_region_variant, intron_variant				ENSP00000501155.1
CAPN3	ENST00000673928.1	c.445-6_445-3delTTTC		splice_region_variant, intron_variant				ENSP00000501099.1
CAPN3	ENST00000674146.1	c.445-6_445-3delTTTC		splice_region_variant, intron_variant				ENSP00000501175.1
CAPN3	ENST00000674149.1	c.445-6_445-3delTTTC		splice_region_variant, intron_variant				ENSP00000501112.1
CAPN3	ENST00000673743.1	c.343-6_343-3delTTTC		splice_region_variant, intron_variant				ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2876-6_*2876-3delTTTC		splice_region_variant, intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 26

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Medical Molecular Genetics Department, National Research Center	Aug 11, 2024	By applying ACMG guidelines: According to insilico studies, the variant is classified as deleterious (PP3),our study patient’s clinical phenotype is typically correlated to the disease (PP4), it showed an extremely low frequency in gnomAD population databases (PS4) Reputable source recently reports variant as pathogenic , but the evidence is not available to the laboratory to perform an independent evaluation (PP5) so according to ACMG guidlines it is classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2022	This sequence change falls in intron 23 of the CAPN3 gene. It does not directly change the encoded amino acid sequence of the CAPN3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 16141003, 17702496). ClinVar contains an entry for this variant (Variation ID: 550740). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 13, 2017	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.47		Position offset: 10

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555423426; hg19: chr15-42703935;