15-42359702-G-C

Position:

• chr15-42359702-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000070.3(CAPN3):​c.-104G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,585,770 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 32)
  • Exomes 𝑓: 0.018 (258 hom.)
• Consequence: CAPN3 NM_000070.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.283

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1874/152322) while in subpopulation NFE AF= 0.019 (1293/68012). AF 95% confidence interval is 0.0182. There are 19 homozygotes in gnomad4. There are 870 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.-104G>C		5_prime_UTR_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.-104G>C		5_prime_UTR_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.-104G>C		5_prime_UTR_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163	c.-104G>C		5_prime_UTR_variant	1/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*105+5249G>C		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1875 AN: 152204 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0176 AC: 25281 AN: 1433448 Hom.: 258 Cov.: 31 AF XY: 0.0171 AC XY: 12201 AN XY: 711714

Gnomad4 AFR exome AF: 0.00289

Gnomad4 AMR exome AF: 0.00908

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00477

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0123 AC: 1874 AN: 152322 Hom.: 19 Cov.: 32 AF XY: 0.0117 AC XY: 870 AN XY: 74488

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0161 Hom.: 2

Bravo AF: 0.0116

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Limb-girdle muscular dystrophy, recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.91

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: rs149698681; hg19: chr15-42651900;