15-42410645-C-G

Position:

• chr15-42410645-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000070.3(CAPN3):​c.2242C>G​(p.Arg748Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,646 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R748Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.21

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 9) in uniprot entity CAN3_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42410646-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 15-42410645-C-G is Pathogenic according to our data. Variant chr15-42410645-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 548138.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2242C>G	p.Arg748Gly	missense_variant	21/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2242C>G	p.Arg748Gly	missense_variant	21/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.247C>G	p.Arg83Gly	missense_variant	8/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.247C>G	p.Arg83Gly	missense_variant	8/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.247C>G	p.Arg83Gly	missense_variant	9/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.247C>G	p.Arg83Gly	missense_variant	8/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.145C>G	p.Arg49Gly	missense_variant	8/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2678C>G		non_coding_transcript_exon_variant	23/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2678C>G		3_prime_UTR_variant	23/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461646 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Neuromuscular Diagnostic Laboratory, American University of Beirut Medical Center

Jul 15, 2017

c.2242C>G (p.Arg748Gly) mutation was identified in a patient diagnosed with Limb girdle muscular dystrophy type 2A (LGMD2A). The diagnosis of LGMD2A was first suspected on the basis of a typical clinical localization of the muscle weakness and further confirmed by immunoblotting and molecular analysis. His family history is pertinent as his parents are maternal cousins, and one his two brothers showed similar but more advanced symptoms. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;.;.;D;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;.;D;.;D;.;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Uncertain	2.7	.;.;.;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.3	.;D;D;D;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.94
MutPred		0.87		.;.;.;Gain of disorder (P = 0.1516);.;.;.;.;.;.;.;.;
MVP		0.88
MPC		0.72
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.95
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs768090444; hg19: chr15-42702843;