rs72468681

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2391T>G(p.Asn797Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,208,031 control chromosomes in the GnomAD database, including 80 homozygotes. There are 4,378 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 2 hom., 221 hem., cov: 24)

Exomes 𝑓: 0.012 ( 78 hom. 4157 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 1.55

Publications

11 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:

ENSG00000297605 (HGNC:):

ENSG00000297605 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=0.008066297).

BP6

Variant X-32491508-A-C is Benign according to our data. Variant chrX-32491508-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94510.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 = 0.00695 (780/112178) while in subpopulation NFE AF = 0.0117 (622/53237). AF 95% confidence interval is 0.0109. There are 2 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 780 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.2391T>G	p.Asn797Lys	missense_variant	Exon 20 of 79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.2391T>G	p.Asn797Lys	missense_variant	Exon 20 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.00697

AC:

782

AN:

112124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00313

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.000277

Gnomad SAS

AF:

0.00221

Gnomad FIN

AF:

0.00721

Gnomad MID

AF:

0.0169

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00794

GnomAD2 exomes

AF:

0.00649

AC:

1158

AN:

178379

AF XY:

0.00652

show subpopulations

Gnomad AFR exome

AF:

0.00201

Gnomad AMR exome

AF:

0.00184

Gnomad ASJ exome

AF:

0.000809

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00700

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00698

GnomAD4 exome

AF:

0.0119

AC:

13021

AN:

1095853

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

4157

AN XY:

361375

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

26352

American (AMR)

AF:

0.00222

AC:

AN:

35125

Ashkenazi Jewish (ASJ)

AF:

0.000671

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30148

South Asian (SAS)

AF:

0.00351

AC:

189

AN:

53870

European-Finnish (FIN)

AF:

0.00678

AC:

273

AN:

40263

Middle Eastern (MID)

AF:

0.00389

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.0142

AC:

11966

AN:

840635

Other (OTH)

AF:

0.00974

AC:

448

AN:

45984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

414

827

1241

1654

2068

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.00695

AC:

780

AN:

112178

Hom.:

Cov.:

AF XY:

0.00644

AC XY:

221

AN XY:

34334

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

30889

American (AMR)

AF:

0.00313

AC:

AN:

10558

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3595

South Asian (SAS)

AF:

0.00221

AC:

AN:

2709

European-Finnish (FIN)

AF:

0.00721

AC:

AN:

6104

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0117

AC:

622

AN:

53237

Other (OTH)

AF:

0.00784

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0101

Hom.:

171

Bravo

AF:

0.00620

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00832

AC:

ExAC

AF:

0.00675

AC:

819

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jul 09, 2020

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.2391T>G (p.Asn797Lys) results in a non-conservative amino acid change located in the Central rod domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 178379 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 997 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as benign (7x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -

Mar 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn797Lys in exon 20 of DMD: This variant is not expected to have clinical sig nificance because it has been identified in 1.2% (432/37288) European (Non-Finni sh) chromosomes by the Exome Aggregation Consortium Sequencing Project (http://e xac.broadinstitute.org/variant/X-32509625-A-C; dbSNP rs72468681). In addition, 5 individuals in this European cohort were homozygous and 141 were hemizygous fo r this variant. -

Sep 24, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 2014

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:6

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Benign:2

Mar 11, 2015

CSER _CC_NCGL, University of Washington

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 19, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

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

Apr 20, 2017

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 3B

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype

Benign:1

Sep 24, 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. -

Duchenne muscular dystrophy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

.;T;.;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.78

T;.;T;T

MetaRNN

Benign

0.0081

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

1.6

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.77

.;N;.;N

REVEL

Benign

0.081

Sift

Benign

0.81

.;T;.;T

Sift4G

Benign

0.46

T;T;T;T

Polyphen

0.86

.;P;.;.

Vest4

0.34

MutPred

0.40

.;.;Gain of ubiquitination at N797 (P = 0.0138);Gain of ubiquitination at N797 (P = 0.0138);

MVP

0.69

MPC

0.10

ClinPred

0.019

GERP RS

0.18

gMVP

0.078

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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