rs773827877

Variant names:

• chr15-42399631-G-A
• rs773827877
• NM_000070.3:c.1333G>A
• CAPN3 p.Gly445Arg

Your query was ambiguous. Multiple possible variants found:

• chr15-42399631-G-A
• chr15-42399631-G-C
• chr15-42399631-G-T

Variant summary

Our verdict is Pathogenic. The variant received 28 ACMG points: 28P and 0B. PS1_Very_Strong PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000070.3(CAPN3):​c.1333G>A​(p.Gly445Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,453,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000953639: Experimental studies have shown that this missense change affects CAPN3 function (PMID:15221789, 17236769, 20635405)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G445E) has been classified as Uncertain significance. The gene CAPN3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 10.0
• Publications: 18 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: Pathogenic. The variant received 28 ACMG points.

• PS1: Transcript NM_000070.3 (CAPN3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000953639: Experimental studies have shown that this missense change affects CAPN3 function (PMID: 15221789, 17236769, 20635405).; SCV004229510: Experiments in patient-derived samples showed absence or significant reduction in CAPN3 protein level/activity in multiple patients. PMID:32342993; SCV002571894: "At least one publication reports experimental evidence evaluating an impact on protein function demonstrating that the variant impacts calpain-3 catalytic activity and intra/intermolecular autolysis (Cerino_2020)."
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 15-42399631-G-A is Pathogenic according to our data. Variant chr15-42399631-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 284515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1333G>A	p.Gly445Arg	missense	Exon 10 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.1333G>A	p.Gly445Arg	missense	Exon 10 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.1189G>A	p.Gly397Arg	missense	Exon 9 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.1333G>A	p.Gly445Arg	missense	Exon 10 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.1333G>A	p.Gly445Arg	missense	Exon 10 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.1189G>A	p.Gly397Arg	missense	Exon 9 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 240268 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453300 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 721774

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.00 AC: 0 AN: 43850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 85564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4850

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1107176

Other (OTH) AF: 0.00 AC: 0 AN: 59956

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (5)
4	-	-	not provided (4)
3	-	-	Muscular dystrophy, limb-girdle, autosomal dominant 4 (3)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.94
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.060		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: rs773827877;

hg19: chr15-42691829;