rs28364364

Positions:

• chr15-42359867-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000070.3(CAPN3):​c.62G>A​(p.Gly21Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,614,104 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (29 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.921

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027940571).
• BP6: Variant 15-42359867-G-A is Benign according to our data. Variant chr15-42359867-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92419.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}. Variant chr15-42359867-G-A is described in Lovd as [Pathogenic]. Variant chr15-42359867-G-A is described in Lovd as [Benign]. Variant chr15-42359867-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1666/152250) while in subpopulation AFR AF= 0.0374 (1555/41528). AF 95% confidence interval is 0.0359. There are 26 homozygotes in gnomad4. There are 752 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.62G>A	p.Gly21Glu	missense_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.62G>A	p.Gly21Glu	missense_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.62G>A	p.Gly21Glu	missense_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.62G>A	p.Gly21Glu	missense_variant	1/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*105+5414G>A		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1658 AN: 152132 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00313 AC: 785 AN: 250790 Hom.: 10 AF XY: 0.00270 AC XY: 366 AN XY: 135788

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00128 AC: 1864 AN: 1461854 Hom.: 29 Cov.: 32 AF XY: 0.00118 AC XY: 857 AN XY: 727228

Gnomad4 AFR exome AF: 0.0377

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.0109 AC: 1666 AN: 152250 Hom.: 26 Cov.: 32 AF XY: 0.0101 AC XY: 752 AN XY: 74444

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00254 Hom.: 6

Bravo AF: 0.0132

ESP6500AA AF: 0.0397 AC: 175

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2012	- -

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

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	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 03, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.93	D;D;D;D
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	0.81	.;L;L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.80, 0.13, 0.70	.;P;B;P
Vest4		0.28
MVP		0.90
MPC		0.34
ClinPred		0.019	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.62

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: rs28364364; hg19: chr15-42652065;