chr15-42410638-C-G

Variant names:

• chr15-42410638-C-G
• rs147774793
• NM_000070.3:c.2235C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000070.3(CAPN3):​c.2235C>G​(p.Tyr745*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,800 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 Lovd as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y745Y) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CAPN3 NM_000070.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.302

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 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-42410638-C-G is Pathogenic according to our data. Variant chr15-42410638-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2235C>G	p.Tyr745*	stop_gained	Exon 21 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2235C>G	p.Tyr745*	stop_gained	Exon 21 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.240C>G	p.Tyr80*	stop_gained	Exon 8 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.240C>G	p.Tyr80*	stop_gained	Exon 8 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.240C>G	p.Tyr80*	stop_gained	Exon 9 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.240C>G	p.Tyr80*	stop_gained	Exon 8 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.138C>G	p.Tyr46*	stop_gained	Exon 8 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2671C>G		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2671C>G		3_prime_UTR_variant	Exon 23 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251234 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727192

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: 0.000150

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.67	D
Vest4		0.89
GERP RS		-3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147774793; hg19: chr15-42702836;