rs2241827

chr15-42402746-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000070.3(CAPN3):c.1537-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,596,904 control chromosomes in the GnomAD database, including 398,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44598 hom., cov: 32)
  • Exomes 𝑓: 0.70 (353734 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.08

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-42402746-T-C is Benign according to our data. Variant chr15-42402746-T-C is described in ClinVar as [Benign]. Clinvar id is 92406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42402746-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1537-48T>C		intron_variant		ENST00000397163.8
CAPN3	NM_024344.2	c.1537-48T>C		intron_variant
CAPN3	NM_173087.2	c.1393-48T>C		intron_variant
CAPN3	NM_173088.2	c.1-48T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1537-48T>C		intron_variant		1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114785 AN: 151966 Hom.: 44544 Cov.: 32

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.757

GnomAD3 exomes AF: 0.682 AC: 168544 AN: 247040 Hom.: 58932 AF XY: 0.687 AC XY: 92014 AN XY: 134008

Gnomad AFR exome AF: 0.935

Gnomad AMR exome AF: 0.608

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.423

Gnomad SAS exome AF: 0.704

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.706

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.696 AC: 1006273 AN: 1444820 Hom.: 353734 Cov.: 28 AF XY: 0.697 AC XY: 502013 AN XY: 719856

Gnomad4 AFR exome AF: 0.943

Gnomad4 AMR exome AF: 0.625

Gnomad4 ASJ exome AF: 0.767

Gnomad4 EAS exome AF: 0.413

Gnomad4 SAS exome AF: 0.707

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.710

GnomAD4 genome AF: 0.755 AC: 114895 AN: 152084 Hom.: 44598 Cov.: 32 AF XY: 0.750 AC XY: 55712 AN XY: 74332

Gnomad4 AFR AF: 0.935

Gnomad4 AMR AF: 0.704

Gnomad4 ASJ AF: 0.773

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.696

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.751

Alfa AF: 0.722 Hom.: 43925

Bravo AF: 0.766

Asia WGS AF: 0.567 AC: 1972 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.50
Dann	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs2241827; hg19: chr15-42694944; COSMIC: COSV58823002; COSMIC: COSV58823002;