rs28364543

Variant names:

• chr15-42411339-T-C
• rs28364543
• NM_000070.3:c.2433T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000070.3(CAPN3):​c.2433T>C​(p.Val811Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,613,906 control chromosomes in the GnomAD database, including 60 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 0.011 (33 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.435
• Publications: 2 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health
• limb-girdle muscular dystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 15-42411339-T-C is Benign according to our data. Variant chr15-42411339-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166793.
• BP7: Synonymous conserved (PhyloP=0.435 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1622/152172) while in subpopulation AFR AF = 0.0377 (1563/41506). AF 95% confidence interval is 0.0361. There are 33 homozygotes in GnomAd4. There are 737 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.2433T>C	p.Val811Val	synonymous	Exon 23 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.2415T>C	p.Val805Val	synonymous	Exon 22 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.2157T>C	p.Val719Val	synonymous	Exon 20 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.2433T>C	p.Val811Val	synonymous	Exon 23 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.2415T>C	p.Val805Val	synonymous	Exon 22 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.2157T>C	p.Val719Val	synonymous	Exon 20 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1616 AN: 152054 Hom.: 32 Cov.: 30

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00268 AC: 675 AN: 251438 AF XY: 0.00203

Gnomad AFR exome AF: 0.0388

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00106 AC: 1555 AN: 1461734 Hom.: 27 Cov.: 32 AF XY: 0.000924 AC XY: 672 AN XY: 727184

African (AFR) AF: 0.0398 AC: 1331 AN: 33470

American (AMR) AF: 0.00105 AC: 47 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111876

Other (OTH) AF: 0.00212 AC: 128 AN: 60388

GnomAD4 genome AF: 0.0107 AC: 1622 AN: 152172 Hom.: 33 Cov.: 30 AF XY: 0.00991 AC XY: 737 AN XY: 74406

African (AFR) AF: 0.0377 AC: 1563 AN: 41506

American (AMR) AF: 0.00216 AC: 33 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67996

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00538 Hom.: 19

Bravo AF: 0.0121

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive limb-girdle muscular dystrophy type 2A (3)
-	-	3	not specified (3)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.2
DANN	Benign	0.78
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs28364543; hg19: chr15-42703537;