15-42359675-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000070.3(CAPN3):c.-131G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 1,543,668 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: CAPN3 NM_000070.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.931

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.-131G>T		5_prime_UTR_variant	1/24	ENST00000397163.8
CAPN3	NM_024344.2	c.-131G>T		5_prime_UTR_variant	1/23
CAPN3	NM_173087.2	c.-131G>T		5_prime_UTR_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.-131G>T		5_prime_UTR_variant	1/24	1	NM_000070.3	P2
CAPN3	ENST00000349748.8	c.-131G>T		5_prime_UTR_variant	1/21	1
CAPN3	ENST00000357568.8	c.-131G>T		5_prime_UTR_variant	1/23	1
CAPN3	ENST00000318023.11	c.-131G>T		5_prime_UTR_variant	1/23	5		A2

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152212 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00909

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000467 AC: 650 AN: 1391338 Hom.: 1 Cov.: 31 AF XY: 0.000453 AC XY: 311 AN XY: 686906

Gnomad4 AFR exome AF: 0.00924

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000403

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152330 Hom.: 3 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74488

Gnomad4 AFR AF: 0.00921

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00338

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 24, 2021

- -

Limb-Girdle Muscular Dystrophy, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.1
Dann	Benign	0.70

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: rs113881834; hg19: chr15-42651873;