rs1555423426

Variant names:

• chr15-42411737-CTTCT-C
• rs1555423426
• NM_000070.3:c.2440-6_2440-3delTTTC

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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: Uncertain_significance. The variant received 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 VariationId is 550740.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.2440-6_2440-3delTTTC		splice_region intron	N/A	NP_000061.1
	CAPN3	NM_024344.2		c.2422-6_2422-3delTTTC		splice_region intron	N/A	NP_077320.1
	CAPN3	NM_173087.2		c.2164-6_2164-3delTTTC		splice_region intron	N/A	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.2440-6_2440-3delTTTC		splice_region intron	N/A	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.2422-6_2422-3delTTTC		splice_region intron	N/A	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.2164-6_2164-3delTTTC		splice_region intron	N/A	ENSP00000183936.4

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

Feb 13, 2017

Counsyl

Significance: Uncertain significance

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.

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 11, 2024

Medical Molecular Genetics Department, National Research Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Pathogenic:1

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555423426; hg19: chr15-42703935;