NM_000070.3:c.1992+110T>C

Variant names:

• chr15-42409490-T-C
• rs3115883
• NM_000070.3:c.1992+110T>C

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.1992+110T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,109,212 control chromosomes in the GnomAD database, including 284,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45566 hom., cov: 32)
  • Exomes 𝑓: 0.70 (238714 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.44
• 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=-0.87).
• BP6: Variant 15-42409490-T-C is Benign according to our data. Variant chr15-42409490-T-C is described in ClinVar as Benign. ClinVar VariationId is 678278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1992+110T>C		intron	N/A	NP_000061.1
	CAPN3	NM_024344.2		c.1974+110T>C		intron	N/A	NP_077320.1
	CAPN3	NM_173087.2		c.1716+110T>C		intron	N/A	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1992+110T>C		intron	N/A	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.1974+110T>C		intron	N/A	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.1716+110T>C		intron	N/A	ENSP00000183936.4

Frequencies

GnomAD3 genomes AF: 0.764 AC: 116154 AN: 152050 Hom.: 45516 Cov.: 32

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.673

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.772

GnomAD4 exome AF: 0.703 AC: 672391 AN: 957044 Hom.: 238714 AF XY: 0.704 AC XY: 345964 AN XY: 491408

African (AFR) AF: 0.938 AC: 22052 AN: 23516

American (AMR) AF: 0.698 AC: 25189 AN: 36080

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 17571 AN: 22472

East Asian (EAS) AF: 0.439 AC: 15360 AN: 35002

South Asian (SAS) AF: 0.728 AC: 51895 AN: 71328

European-Finnish (FIN) AF: 0.660 AC: 33083 AN: 50098

Middle Eastern (MID) AF: 0.781 AC: 3747 AN: 4800

European-Non Finnish (NFE) AF: 0.705 AC: 472170 AN: 670158

Other (OTH) AF: 0.719 AC: 31324 AN: 43590

GnomAD4 genome AF: 0.764 AC: 116263 AN: 152168 Hom.: 45566 Cov.: 32 AF XY: 0.759 AC XY: 56431 AN XY: 74382

African (AFR) AF: 0.933 AC: 38778 AN: 41556

American (AMR) AF: 0.732 AC: 11198 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 2744 AN: 3470

East Asian (EAS) AF: 0.436 AC: 2243 AN: 5150

South Asian (SAS) AF: 0.708 AC: 3410 AN: 4816

European-Finnish (FIN) AF: 0.673 AC: 7114 AN: 10578

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48222 AN: 67990

Other (OTH) AF: 0.767 AC: 1618 AN: 2110

Alfa AF: 0.729 Hom.: 77593

Bravo AF: 0.776

Asia WGS AF: 0.586 AC: 2038 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 14, 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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.092
DANN	Benign	0.42
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3115883; hg19: chr15-42701688; COSMIC: COSV55518327; COSMIC: COSV55518327;