rs141934227

chr15-42392710-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000070.3(CAPN3):c.1017G>A(p.Thr339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,613,690 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (7 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.47

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-42392710-G-A is Benign according to our data. Variant chr15-42392710-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 288393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42392710-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.47 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1017G>A	p.Thr339=	synonymous_variant	7/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1017G>A	p.Thr339=	synonymous_variant	7/23
CAPN3	NM_173087.2	c.873G>A	p.Thr291=	synonymous_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1017G>A	p.Thr339=	synonymous_variant	7/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000630 AC: 158 AN: 250976 Hom.: 3 AF XY: 0.000877 AC XY: 119 AN XY: 135682

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: 0.00490

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000345 AC: 504 AN: 1461396 Hom.: 7 Cov.: 31 AF XY: 0.000475 AC XY: 345 AN XY: 727016

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00514

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000549 Hom.: 0

Bravo AF: 0.0000529

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	2.5
Dann	Benign	0.80

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: rs141934227; hg19: chr15-42684908;