rs201012232

Positions:

• chr15-42410648-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000070.3(CAPN3):​c.2245A>C​(p.Asn749His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,756 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

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 Likely_pathogenic. Variant got 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2245A>C	p.Asn749His	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.2245A>C	p.Asn749His	missense_variant	21/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.250A>C	p.Asn84His	missense_variant	8/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.250A>C	p.Asn84His	missense_variant	8/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.250A>C	p.Asn84His	missense_variant	9/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.250A>C	p.Asn84His	missense_variant	8/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.148A>C	p.Asn50His	missense_variant	8/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2681A>C		non_coding_transcript_exon_variant	23/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2681A>C		3_prime_UTR_variant	23/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461756 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;.;D;.;D;.;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	.;.;.;L;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	.;N;N;N;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.12	.;T;T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	.;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.67
MutPred		0.80		.;.;.;Loss of stability (P = 0.1112);.;.;.;.;.;.;.;.;
MVP		0.90
MPC		0.64
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.57
gMVP		0.72

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: rs201012232; hg19: chr15-42702846;