X-32468689-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004006.3(DMD):c.2971G>C(p.Glu991Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,208,762 control chromosomes in the GnomAD database, including 1 homozygotes. There are 765 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E991V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., 55 hem., cov: 22)

Exomes 𝑓: 0.0021 ( 1 hom. 710 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.01

Publications

9 publications found

Variant links:

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

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0083191395).

BP6

Variant X-32468689-C-G is Benign according to our data. Variant chrX-32468689-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00147 (164/111423) while in subpopulation NFE AF = 0.00211 (112/53052). AF 95% confidence interval is 0.00179. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 164 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.2971G>C	p.Glu991Gln	missense_variant	Exon 23 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.2971G>C	p.Glu991Gln	missense_variant	Exon 23 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

164

AN:

111365

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00400

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00211

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00146

AC:

266

AN:

181591

AF XY:

0.00159

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.000513

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00363

Gnomad NFE exome

AF:

0.00226

Gnomad OTH exome

AF:

0.00224

GnomAD4 exome

AF:

0.00207

AC:

2270

AN:

1097339

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

710

AN XY:

362843

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26382

American (AMR)

AF:

0.000512

AC:

AN:

35163

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30159

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54064

European-Finnish (FIN)

AF:

0.00422

AC:

171

AN:

40485

Middle Eastern (MID)

AF:

0.000728

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.00237

AC:

1993

AN:

841550

Other (OTH)

AF:

0.00176

AC:

AN:

46044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

156

235

313

391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00147

AC:

164

AN:

111423

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

AN XY:

33643

show subpopulations

African (AFR)

AF:

0.000293

AC:

AN:

30762

American (AMR)

AF:

0.00183

AC:

AN:

10362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2653

European-Finnish (FIN)

AF:

0.00400

AC:

AN:

6001

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00211

AC:

112

AN:

53052

Other (OTH)

AF:

0.00

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00172

Hom.:

Bravo

AF:

0.00137

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00157

AC:

191

EpiCase

AF:

0.00241

EpiControl

AF:

0.00340

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 22, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 07, 2022

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.2971G>C (p.Glu991Gln) results in a conservative amino acid change located in the Central rod domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 203389 control chromosomes, including 116 hemizygotes (gnomAD). The observed variant frequency is approximately 131 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies (1.1e-05), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign. -

Aug 04, 2014

Eurofins Ntd Llc (ga)

Significance:Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 21, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19937601, 25163546, 27977773, 14695533) -

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

Benign:1

Jun 24, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Duchenne muscular dystrophy

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 27, 2017

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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

.;T;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;.;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.0083

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

7.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

.;N;.;N

REVEL

Benign

0.067

Sift

Benign

0.16

.;T;.;T

Sift4G

Benign

0.098

T;T;T;T

Polyphen

0.92

.;P;.;.

Vest4

0.44

MVP

0.67

MPC

0.020

ClinPred

0.048

GERP RS

5.1

gMVP

0.12

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over