rs28364441

Positions:

• chr15-42392677-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000070.3(CAPN3):​c.984C>T​(p.Cys328Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00732 in 1,613,836 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (56 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.90

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-42392677-C-T is Benign according to our data. Variant chr15-42392677-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 166787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42392677-C-T is described in Lovd as [Likely_benign]. Variant chr15-42392677-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.9 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.984C>T	p.Cys328Cys	synonymous_variant	7/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.984C>T	p.Cys328Cys	synonymous_variant	7/23		NP_077320.1
CAPN3	NM_173087.2	c.840C>T	p.Cys280Cys	synonymous_variant	6/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.984C>T	p.Cys328Cys	synonymous_variant	7/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*780C>T		non_coding_transcript_exon_variant	11/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*780C>T		3_prime_UTR_variant	11/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 885 AN: 152138 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00966

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00582 AC: 1461 AN: 251202 Hom.: 12 AF XY: 0.00576 AC XY: 782 AN XY: 135786

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00748 AC: 10935 AN: 1461580 Hom.: 56 Cov.: 31 AF XY: 0.00719 AC XY: 5227 AN XY: 727094

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00910

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.00581 AC: 885 AN: 152256 Hom.: 7 Cov.: 32 AF XY: 0.00555 AC XY: 413 AN XY: 74446

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00966

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00823 Hom.: 5

Bravo AF: 0.00640

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00883

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CAPN3: BP4, BP7, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 08, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.3
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs28364441; hg19: chr15-42684875;