15-42359824-G-C

Position:

• chr15-42359824-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000070.3(CAPN3):​c.19G>C​(p.Ala7Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.518

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0550493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.19G>C	p.Ala7Pro	missense_variant	1/24	ENST00000397163.8
CAPN3	NM_024344.2	c.19G>C	p.Ala7Pro	missense_variant	1/23
CAPN3	NM_173087.2	c.19G>C	p.Ala7Pro	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.19G>C	p.Ala7Pro	missense_variant	1/24	1	NM_000070.3	P2
CAPN3	ENST00000357568.8	c.19G>C	p.Ala7Pro	missense_variant	1/23	1
CAPN3	ENST00000349748.8	c.19G>C	p.Ala7Pro	missense_variant	1/21	1
CAPN3	ENST00000318023.11	c.19G>C	p.Ala7Pro	missense_variant	1/23	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2017	The A7P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A7P variant is not observed in large population cohorts (Lek et al., 2016). The A7P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Missense variants in nearby residues (T3N, V4I) have been reported in the Human Gene Mutation Database in association with limb girdle muscular dystrophy (Stenson et al., 2014). However, this substitution occurs at a position that is not conserved, and Proline is observed at this position in evolution. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.040
DANN	Benign	0.87
DEOGEN2	Benign	0.0085	T;.;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	0.98	D;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.20	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.30	T;T;T;T
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.011, 0.037, 0.0060	.;B;B;B
Vest4		0.12
MutPred		0.19		Loss of MoRF binding (P = 0.0299);Loss of MoRF binding (P = 0.0299);Loss of MoRF binding (P = 0.0299);Loss of MoRF binding (P = 0.0299);
MVP		0.51
MPC		0.19
ClinPred		0.27	T
GERP RS		-11
Varity_R		0.058
gMVP		0.60

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: rs776827432; hg19: chr15-42652022;