15-42403763-G-C

Variant names:

• chr15-42403763-G-C
• rs370809015
• NM_000070.3:c.1768G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000070.3(CAPN3):​c.1768G>C​(p.Val590Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V590M) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.58

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21458414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1768G>C	p.Val590Leu	missense_variant	Exon 14 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1768G>C	p.Val590Leu	missense_variant	Exon 14 of 23		NP_077320.1
CAPN3	NM_173087.2	c.1624G>C	p.Val542Leu	missense_variant	Exon 13 of 21		NP_775110.1
CAPN3	NM_173088.2	c.232G>C	p.Val78Leu	missense_variant	Exon 3 of 13		NP_775111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1768G>C	p.Val590Leu	missense_variant	Exon 14 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*2222G>C		non_coding_transcript_exon_variant	Exon 17 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2222G>C		3_prime_UTR_variant	Exon 17 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0088
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.90	.;L;.;L;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	.;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.065	.;T;T;T;T;D
Sift4G	Benign	0.61	T;T;T;T;T;T
Polyphen		0.0080, 0.0040	.;B;B;B;.;.
Vest4		0.27
MutPred		0.30		.;Loss of MoRF binding (P = 0.1056);.;Loss of MoRF binding (P = 0.1056);.;.;
MVP		0.86
MPC		0.14
ClinPred		0.76	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs370809015; hg19: chr15-42695961;