rs1555423200

Positions:

• chr15-42410915-CATT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_000070.3(CAPN3):​c.2297_2299delTTA​(p.Ile766del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 10) in uniprot entity CAN3_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000070.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2297_2299delTTA	p.Ile766del	disruptive_inframe_deletion	22/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2297_2299delTTA	p.Ile766del	disruptive_inframe_deletion	22/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.302_304delTTA	p.Ile101del	disruptive_inframe_deletion	9/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.302_304delTTA	p.Ile101del	disruptive_inframe_deletion	9/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.302_304delTTA	p.Ile101del	disruptive_inframe_deletion	10/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.302_304delTTA	p.Ile101del	disruptive_inframe_deletion	9/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.200_202delTTA	p.Ile67del	disruptive_inframe_deletion	9/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2733_*2735delTTA		non_coding_transcript_exon_variant	24/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2733_*2735delTTA		3_prime_UTR_variant	24/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 30, 2018

- -

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: rs1555423200; hg19: chr15-42703113;