15-42399466-C-G

Variant names:

• chr15-42399466-C-G
• rs3743003
• NM_000070.3:c.1194-26C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000070.3(CAPN3):​c.1194-26C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,595,970 control chromosomes in the GnomAD database, including 5,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2612 hom., cov: 31)
  • Exomes 𝑓: 0.048 (3347 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.60
• Publications: 7 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-42399466-C-G is Benign according to our data. Variant chr15-42399466-C-G is described in ClinVar as Benign. ClinVar VariationId is 254857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1194-26C>G		intron_variant	Intron 9 of 23	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1194-26C>G		intron_variant	Intron 9 of 22		NP_077320.1
CAPN3	NM_173087.2	c.1050-26C>G		intron_variant	Intron 8 of 20		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1194-26C>G		intron_variant	Intron 9 of 23	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*990-26C>G		intron_variant	Intron 13 of 25	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18870 AN: 152004 Hom.: 2593 Cov.: 31

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0585

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0386

Gnomad OTH AF: 0.0952

GnomAD2 exomes AF: 0.0587 AC: 14765 AN: 251422 AF XY: 0.0538

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.0529

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0387

Gnomad OTH exome AF: 0.0448

GnomAD4 exome AF: 0.0477 AC: 68936 AN: 1443848 Hom.: 3347 Cov.: 28 AF XY: 0.0469 AC XY: 33772 AN XY: 719360

African (AFR) AF: 0.352 AC: 11528 AN: 32730

American (AMR) AF: 0.0342 AC: 1528 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 559 AN: 26046

East Asian (EAS) AF: 0.0611 AC: 2418 AN: 39604

South Asian (SAS) AF: 0.0515 AC: 4388 AN: 85162

European-Finnish (FIN) AF: 0.0234 AC: 1250 AN: 53374

Middle Eastern (MID) AF: 0.0408 AC: 234 AN: 5740

European-Non Finnish (NFE) AF: 0.0398 AC: 43679 AN: 1096738

Other (OTH) AF: 0.0561 AC: 3352 AN: 59762

GnomAD4 genome AF: 0.124 AC: 18934 AN: 152122 Hom.: 2612 Cov.: 31 AF XY: 0.121 AC XY: 9009 AN XY: 74370

African (AFR) AF: 0.346 AC: 14315 AN: 41432

American (AMR) AF: 0.0532 AC: 814 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.0586 AC: 304 AN: 5184

South Asian (SAS) AF: 0.0618 AC: 296 AN: 4788

European-Finnish (FIN) AF: 0.0254 AC: 269 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0386 AC: 2627 AN: 68016

Other (OTH) AF: 0.0947 AC: 200 AN: 2112

Alfa AF: 0.0873 Hom.: 187

Bravo AF: 0.136

Asia WGS AF: 0.0850 AC: 294 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.29
DANN	Benign	0.45
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3743003; hg19: chr15-42691664;