rs28364441

Variant names:

• chr15-42392677-C-T
• rs28364441
• NM_000070.3:c.984C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -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 Benign/Likely_benign. ClinVar VariationId is 166787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.9 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR,SD 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.984C>T	p.Cys328Cys	synonymous	Exon 7 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.984C>T	p.Cys328Cys	synonymous	Exon 7 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.840C>T	p.Cys280Cys	synonymous	Exon 6 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.984C>T	p.Cys328Cys	synonymous	Exon 7 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.984C>T	p.Cys328Cys	synonymous	Exon 7 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.840C>T	p.Cys280Cys	synonymous	Exon 6 of 21	ENSP00000183936.4	P20807-2

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

GnomAD2 exomes AF: 0.00582 AC: 1461 AN: 251202 AF XY: 0.00576

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 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

African (AFR) AF: 0.00131 AC: 44 AN: 33466

American (AMR) AF: 0.00436 AC: 195 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86244

European-Finnish (FIN) AF: 0.00185 AC: 99 AN: 53392

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5764

European-Non Finnish (NFE) AF: 0.00910 AC: 10120 AN: 1111804

Other (OTH) AF: 0.00648 AC: 391 AN: 60374

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

African (AFR) AF: 0.00183 AC: 76 AN: 41544

American (AMR) AF: 0.00778 AC: 119 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00966 AC: 657 AN: 68032

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00784 Hom.: 5

Bravo AF: 0.00640

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00883

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Autosomal recessive limb-girdle muscular dystrophy type 2A (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.3
DANN	Benign	0.87
PhyloP100		-3.9
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs28364441; hg19: chr15-42684875;