rs2289293

Variant names:

• chr15-42408354-G-A
• rs2289293
• NM_000070.3:c.1914+30G>A

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.1914+30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,414,414 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (604 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (575 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.01
• Publications: 2 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 (MetaRNN=0.0016736388).
• BP6: Variant 15-42408354-G-A is Benign according to our data. Variant chr15-42408354-G-A is described in ClinVar as [Benign]. Clinvar id is 254864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1914+30G>A		intron_variant	Intron 16 of 23	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1914+30G>A		intron_variant	Intron 16 of 23	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.-82+30G>A		intron_variant	Intron 3 of 10			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.-82+214G>A		intron_variant	Intron 3 of 10			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.-82+30G>A		intron_variant	Intron 4 of 11			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.-82+30G>A		intron_variant	Intron 3 of 10			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.-179+214G>A		intron_variant	Intron 3 of 10			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2350+30G>A		intron_variant	Intron 18 of 25	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7621 AN: 152164 Hom.: 598 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.0353

GnomAD2 exomes AF: 0.0192 AC: 4749 AN: 247870 AF XY: 0.0163

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.00687

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.0519

Gnomad FIN exome AF: 0.000235

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00974

GnomAD4 exome AF: 0.00899 AC: 11342 AN: 1262134 Hom.: 575 Cov.: 18 AF XY: 0.00877 AC XY: 5591 AN XY: 637512

African (AFR) AF: 0.172 AC: 5129 AN: 29808

American (AMR) AF: 0.00831 AC: 367 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.00181 AC: 45 AN: 24812

East Asian (EAS) AF: 0.0606 AC: 2342 AN: 38640

South Asian (SAS) AF: 0.0221 AC: 1818 AN: 82080

European-Finnish (FIN) AF: 0.000340 AC: 18 AN: 52896

Middle Eastern (MID) AF: 0.0110 AC: 59 AN: 5382

European-Non Finnish (NFE) AF: 0.000762 AC: 709 AN: 930754

Other (OTH) AF: 0.0159 AC: 855 AN: 53606

GnomAD4 genome AF: 0.0502 AC: 7652 AN: 152280 Hom.: 604 Cov.: 32 AF XY: 0.0490 AC XY: 3650 AN XY: 74472

African (AFR) AF: 0.165 AC: 6836 AN: 41534

American (AMR) AF: 0.0147 AC: 225 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.0554 AC: 287 AN: 5178

South Asian (SAS) AF: 0.0281 AC: 136 AN: 4832

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68018

Other (OTH) AF: 0.0350 AC: 74 AN: 2116

Alfa AF: 0.0310 Hom.: 68

Bravo AF: 0.0556

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.153 AC: 672

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0224 AC: 2716

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.6
DANN	Benign	0.91
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0017	T
PhyloP100		1.0
PROVEAN	Benign	-0.20	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
GERP RS		1.7
PromoterAI		-0.0048	Neutral
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: rs2289293; hg19: chr15-42700552;