X-32545146-A-G

Variant names:

• chrX-32545146-A-G
• rs228373
• NM_004006.3:c.2168+13T>C

Variant summary

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

The NM_004006.3(DMD):​c.2168+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,203,283 control chromosomes in the GnomAD database, including 31,458 homozygotes. There are 103,963 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (4627 hom., 10534 hem., cov: 23)
  • Exomes 𝑓: 0.26 (26831 hom. 93429 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.890
• Publications: 11 publications found

Genes affected

DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]

DMD Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-32545146-A-G is Benign according to our data. Variant chrX-32545146-A-G is described in ClinVar as Benign. ClinVar VariationId is 94495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.2168+13T>C		intron_variant	Intron 17 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.2168+13T>C		intron_variant	Intron 17 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.323 AC: 35839 AN: 111110 Hom.: 4620 Cov.: 23

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.313 AC: 56257 AN: 180013 AF XY: 0.299

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.537

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.260 AC: 284460 AN: 1092120 Hom.: 26831 Cov.: 30 AF XY: 0.261 AC XY: 93429 AN XY: 358552

African (AFR) AF: 0.475 AC: 12472 AN: 26258

American (AMR) AF: 0.394 AC: 13785 AN: 35018

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 5206 AN: 19328

East Asian (EAS) AF: 0.523 AC: 15768 AN: 30133

South Asian (SAS) AF: 0.304 AC: 16428 AN: 53962

European-Finnish (FIN) AF: 0.278 AC: 11250 AN: 40420

Middle Eastern (MID) AF: 0.345 AC: 1380 AN: 3998

European-Non Finnish (NFE) AF: 0.233 AC: 195283 AN: 837162

Other (OTH) AF: 0.281 AC: 12888 AN: 45841

GnomAD4 genome AF: 0.323 AC: 35881 AN: 111163 Hom.: 4627 Cov.: 23 AF XY: 0.315 AC XY: 10534 AN XY: 33449

African (AFR) AF: 0.468 AC: 14277 AN: 30530

American (AMR) AF: 0.338 AC: 3533 AN: 10464

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 716 AN: 2637

East Asian (EAS) AF: 0.547 AC: 1894 AN: 3463

South Asian (SAS) AF: 0.313 AC: 840 AN: 2680

European-Finnish (FIN) AF: 0.262 AC: 1570 AN: 5998

Middle Eastern (MID) AF: 0.243 AC: 53 AN: 218

European-Non Finnish (NFE) AF: 0.234 AC: 12397 AN: 52969

Other (OTH) AF: 0.327 AC: 498 AN: 1521

Alfa AF: 0.276 Hom.: 32020

Bravo AF: 0.342

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 12, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DMD c.2168+13T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.32 in 82561 control chromosomes in the ExAC database, including 3112 homozygotes. The observed variant frequency is approximately 28.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophiopathies phenotype (0.011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2168+13T>C in individuals affected with Dystrophiopathies and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Nov 22, 2013

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. -

Apr 24, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2168+13T>C in intron 17 of DMD: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 47.4% (1816/3833) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs228373). -

Dilated cardiomyopathy 3B Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1

Aug 09, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs228373; hg19: chrX-32563263; COSMIC: COSV55873249;