rs121434547

Variant names:

• chr15-42392649-C-G
• rs121434547
• NM_000070.3:c.956C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-42392649-C-G
• chr15-42392649-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_000070.3(CAPN3):​c.956C>G​(p.Pro319Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P319L) has been classified as Likely pathogenic. The gene CAPN3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.80
• Publications: 0 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

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

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42392649-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 15-42392649-C-G is Pathogenic according to our data. Variant chr15-42392649-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2913353.Status of the report is criteria_provided_single_submitter, 1 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.956C>G	p.Pro319Arg	missense	Exon 7 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.956C>G	p.Pro319Arg	missense	Exon 7 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.812C>G	p.Pro271Arg	missense	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.956C>G	p.Pro319Arg	missense	Exon 7 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.956C>G	p.Pro319Arg	missense	Exon 7 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.812C>G	p.Pro271Arg	missense	Exon 6 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461030 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726866

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111344

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.069
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.96	L
PhyloP100		4.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.61
Sift	Benign	0.051	T
Sift4G	Benign	0.070	T
Polyphen		0.062	B
Vest4		0.61
MutPred		0.67		Gain of MoRF binding (P = 6e-04)
MVP		0.97
MPC		0.63
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.33
gMVP		0.83
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121434547; hg19: chr15-42684847;