NM_004006.3:c.7243C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004006.3(DMD):c.7243C>T(p.Arg2415Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,209,890 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2415H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., 10 hem., cov: 24)

Exomes 𝑓: 0.000069 ( 0 hom. 22 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.42

Publications

1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011680812).

BP6

Variant X-31820041-G-A is Benign according to our data. Variant chrX-31820041-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166702.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000447 (50/111931) while in subpopulation AFR AF = 0.00149 (46/30811). AF 95% confidence interval is 0.00115. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 50 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.7243C>T	p.Arg2415Cys	missense_variant	Exon 50 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.7243C>T	p.Arg2415Cys	missense_variant	Exon 50 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.000438

AC:

AN:

111874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000213

AC:

AN:

183490

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000976

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000692

AC:

AN:

1097959

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

363315

show subpopulations

African (AFR)

AF:

0.00174

AC:

AN:

26398

American (AMR)

AF:

0.0000852

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

841884

Other (OTH)

AF:

0.000152

AC:

AN:

46082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000447

AC:

AN:

111931

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

AN XY:

34117

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

30811

American (AMR)

AF:

0.0000948

AC:

AN:

10550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.000283

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6081

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53201

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000135

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.00157

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

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 02, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 29, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Jan 22, 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

0.071

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

.;.;T;.;.

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.67

T;T;.;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

2.4

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.7

N;.;N;.;N

REVEL

Benign

0.13

Sift

Benign

0.15

T;.;T;.;T

Sift4G

Benign

0.18

T;T;T;T;T

Polyphen

0.0

.;.;B;.;.

Vest4

0.20, 0.14, 0.17, 0.12

MVP

0.42

MPC

0.017

ClinPred

0.022

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.16

Mutation Taster

=97/3

polymorphism

(source)

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

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