rs28364538

Variant names:

• chr15-42411011-GA-G
• rs28364538
• NM_000070.3:c.2380+12delA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000070.3(CAPN3):​c.2380+12delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 1,592,214 control chromosomes in the GnomAD database, including 3,022 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). The gene CAPN3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.045 (223 hom., cov: 31)
  • Exomes 𝑓: 0.060 (2799 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.657
• Publications: 10 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: Orphanet, Labcorp Genetics (formerly Invitae), 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000258461 (HGNC:):

ACMG classification

Specifications for CAPN3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-42411011-GA-G is Benign according to our data. Variant chr15-42411011-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

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.2380+12delA		intron	N/A	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.2362+12delA		intron	N/A	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.2104+12delA		intron	N/A	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.2380+12delA		intron	N/A	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.2362+12delA		intron	N/A	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.2104+12delA		intron	N/A	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.0452 AC: 6877 AN: 152220 Hom.: 224 Cov.: 31

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0516

GnomAD2 exomes AF: 0.0461 AC: 11569 AN: 251222 AF XY: 0.0465

Gnomad AFR exome AF: 0.00966

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.0637

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0617

Gnomad NFE exome AF: 0.0650

Gnomad OTH exome AF: 0.0524

GnomAD4 exome AF: 0.0596 AC: 85854 AN: 1439876 Hom.: 2799 Cov.: 26 AF XY: 0.0588 AC XY: 42213 AN XY: 717780

African (AFR) AF: 0.00794 AC: 262 AN: 32996

American (AMR) AF: 0.0308 AC: 1376 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0653 AC: 1698 AN: 25986

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39554

South Asian (SAS) AF: 0.0252 AC: 2165 AN: 85828

European-Finnish (FIN) AF: 0.0616 AC: 3285 AN: 53368

Middle Eastern (MID) AF: 0.0342 AC: 196 AN: 5734

European-Non Finnish (NFE) AF: 0.0673 AC: 73457 AN: 1092046

Other (OTH) AF: 0.0571 AC: 3408 AN: 59666

GnomAD4 genome AF: 0.0451 AC: 6873 AN: 152338 Hom.: 223 Cov.: 31 AF XY: 0.0439 AC XY: 3268 AN XY: 74476

African (AFR) AF: 0.0118 AC: 491 AN: 41588

American (AMR) AF: 0.0388 AC: 593 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 225 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4832

European-Finnish (FIN) AF: 0.0701 AC: 744 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0662 AC: 4503 AN: 68022

Other (OTH) AF: 0.0510 AC: 108 AN: 2116

Alfa AF: 0.0413 Hom.: 43

Bravo AF: 0.0414

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Autosomal recessive limb-girdle muscular dystrophy type 2A (4)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
Mutation Taster		=95/5	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28364538;

hg19: chr15-42703209;