rs1801188

Variant names:

• chrX-31679519-A-G
• rs1801188
• NM_004006.3:c.7728T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004006.3(DMD):​c.7728T>C​(p.Asn2576Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,209,378 control chromosomes in the GnomAD database, including 16,866 homozygotes. There are 77,011 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1216 hom., 5077 hem., cov: 23)
  • Exomes 𝑓: 0.20 (15650 hom. 71934 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.08
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-31679519-A-G is Benign according to our data. Variant chrX-31679519-A-G is described in ClinVar as Benign. ClinVar VariationId is 94776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.7728T>C	p.Asn2576Asn	synonymous_variant	Exon 53 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.7728T>C	p.Asn2576Asn	synonymous_variant	Exon 53 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.162 AC: 18031 AN: 111445 Hom.: 1217 Cov.: 23

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.235

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.170 AC: 31122 AN: 183044 AF XY: 0.173

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0828

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.348

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.199 AC: 218828 AN: 1097879 Hom.: 15650 Cov.: 31 AF XY: 0.198 AC XY: 71934 AN XY: 363295

African (AFR) AF: 0.0945 AC: 2495 AN: 26395

American (AMR) AF: 0.0902 AC: 3174 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 3489 AN: 19384

East Asian (EAS) AF: 0.399 AC: 12042 AN: 30199

South Asian (SAS) AF: 0.143 AC: 7736 AN: 54141

European-Finnish (FIN) AF: 0.131 AC: 5312 AN: 40477

Middle Eastern (MID) AF: 0.202 AC: 837 AN: 4137

European-Non Finnish (NFE) AF: 0.207 AC: 174517 AN: 841862

Other (OTH) AF: 0.200 AC: 9226 AN: 46080

GnomAD4 genome AF: 0.162 AC: 18039 AN: 111499 Hom.: 1216 Cov.: 23 AF XY: 0.151 AC XY: 5077 AN XY: 33721

African (AFR) AF: 0.0954 AC: 2935 AN: 30779

American (AMR) AF: 0.140 AC: 1471 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 461 AN: 2643

East Asian (EAS) AF: 0.360 AC: 1249 AN: 3469

South Asian (SAS) AF: 0.137 AC: 368 AN: 2682

European-Finnish (FIN) AF: 0.115 AC: 688 AN: 5985

Middle Eastern (MID) AF: 0.226 AC: 49 AN: 217

European-Non Finnish (NFE) AF: 0.197 AC: 10455 AN: 53001

Other (OTH) AF: 0.188 AC: 285 AN: 1516

Alfa AF: 0.191 Hom.: 4163

Bravo AF: 0.161

EpiCase AF: 0.203

EpiControl AF: 0.206

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Oct 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn2576Asn in exon 53 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 20% (1364/6728) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs1801188). -

Aug 03, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 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. -

Feb 18, 2019

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.7728T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.17 in 204704 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.35 in the gnomAD database, including 584 homozygotes and 1751 hemizygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (0.011), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.7728T>C in individuals affected with Dystrophinopathies and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

Apr 22, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Benign:3

Aug 01, 2017

Phosphorus, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Dilated cardiomyopathy 3B Benign:2

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

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

Apr 20, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 29, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.0
DANN	Benign	0.66
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1801188; hg19: chrX-31697636; COSMIC: COSV58894615;