rs35889956

Positions:

• chr15-42387805-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM5 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000070.3(CAPN3):​c.551C>T​(p.Thr184Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,142 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T184R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0094 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (17 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 7.91

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42387805-C-G is described in Lovd as [Likely_pathogenic].
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.012169331).
• BP6: Variant 15-42387805-C-T is Benign according to our data. Variant chr15-42387805-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42387805-C-T is described in Lovd as [Pathogenic]. Variant chr15-42387805-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-42387805-C-T is described in Lovd as [Likely_benign]. Variant chr15-42387805-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00938 (1428/152276) while in subpopulation AFR AF= 0.0332 (1380/41550). AF 95% confidence interval is 0.0318. There are 26 homozygotes in gnomad4. There are 631 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.551C>T	p.Thr184Met	missense_variant	4/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.551C>T	p.Thr184Met	missense_variant	4/23		NP_077320.1
CAPN3	NM_173087.2	c.551C>T	p.Thr184Met	missense_variant	4/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.551C>T	p.Thr184Met	missense_variant	4/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*347C>T		non_coding_transcript_exon_variant	8/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*347C>T		3_prime_UTR_variant	8/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 1425 AN: 152158 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00242 AC: 608 AN: 251442 Hom.: 13 AF XY: 0.00163 AC XY: 221 AN XY: 135892

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000870 AC: 1272 AN: 1461866 Hom.: 17 Cov.: 32 AF XY: 0.000766 AC XY: 557 AN XY: 727234

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00938 AC: 1428 AN: 152276 Hom.: 26 Cov.: 32 AF XY: 0.00847 AC XY: 631 AN XY: 74476

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00194 Hom.: 10

Bravo AF: 0.0107

ESP6500AA AF: 0.0365 AC: 161

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00310 AC: 376

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: CAPN3 c.551C>T (p.Thr184Met) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 251442 control chromosomes, predominantly at a frequency of 0.035 within the African or African-American subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as benign and one as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2016	- -

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	- -
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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2020	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;.;.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.7	.;M;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.86
MVP		0.98
MPC		0.64
ClinPred		0.031	T
GERP RS		5.9
Varity_R		0.40
gMVP		0.83

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: rs35889956; hg19: chr15-42680003;