rs1800275

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.7096A>C(p.Lys2366Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,200,242 control chromosomes in the GnomAD database, including 21,883 homozygotes. There are 83,031 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 1952 hom., 6801 hem., cov: 23)

Exomes 𝑓: 0.22 ( 19931 hom. 76230 hem. )

Consequence

DMD
NM_004006.3 missense, splice_region

Scores

Splicing: ADA: 0.06784

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.61

Publications

25 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=0.0033306181).

BP6

Variant X-31875190-T-G is Benign according to our data. Variant chrX-31875190-T-G is described in ClinVar as Benign. ClinVar VariationId is 166706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.7096A>C	p.Lys2366Gln	missense_variant, splice_region_variant	Exon 48 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.7096A>C	p.Lys2366Gln	missense_variant, splice_region_variant	Exon 48 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

23299

AN:

111060

Hom.:

1954

Cov.:

show subpopulations

Gnomad AFR

AF:

0.168

Gnomad AMI

AF:

0.321

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.224

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.221

GnomAD2 exomes

AF:

0.234

AC:

39146

AN:

167586

AF XY:

0.199

show subpopulations

Gnomad AFR exome

AF:

0.171

Gnomad AMR exome

AF:

0.516

Gnomad ASJ exome

AF:

0.189

Gnomad EAS exome

AF:

0.0987

Gnomad FIN exome

AF:

0.192

Gnomad NFE exome

AF:

0.208

Gnomad OTH exome

AF:

0.206

GnomAD4 exome

AF:

0.219

AC:

238860

AN:

1089132

Hom.:

19931

Cov.:

AF XY:

0.214

AC XY:

76230

AN XY:

356672

show subpopulations

African (AFR)

AF:

0.171

AC:

4469

AN:

26153

American (AMR)

AF:

0.506

AC:

17162

AN:

33932

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

3729

AN:

19166

East Asian (EAS)

AF:

0.0868

AC:

2610

AN:

30064

South Asian (SAS)

AF:

0.151

AC:

7960

AN:

52666

European-Finnish (FIN)

AF:

0.197

AC:

7935

AN:

40246

Middle Eastern (MID)

AF:

0.229

AC:

930

AN:

4062

European-Non Finnish (NFE)

AF:

0.221

AC:

184655

AN:

837126

Other (OTH)

AF:

0.206

AC:

9410

AN:

45717

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

5572

11143

16715

22286

27858

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6768

13536

20304

27072

33840

<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:

0.210

AC:

23297

AN:

111110

Hom.:

1952

Cov.:

AF XY:

0.204

AC XY:

6801

AN XY:

33362

show subpopulations

African (AFR)

AF:

0.169

AC:

5174

AN:

30689

American (AMR)

AF:

0.384

AC:

3963

AN:

10327

Ashkenazi Jewish (ASJ)

AF:

0.184

AC:

487

AN:

2642

East Asian (EAS)

AF:

0.102

AC:

358

AN:

3525

South Asian (SAS)

AF:

0.128

AC:

340

AN:

2657

European-Finnish (FIN)

AF:

0.189

AC:

1125

AN:

5949

Middle Eastern (MID)

AF:

0.199

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.213

AC:

11265

AN:

52927

Other (OTH)

AF:

0.217

AC:

329

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

657

1315

1972

2630

3287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.209

Hom.:

14805

Bravo

AF:

0.231

TwinsUK

AF:

0.228

AC:

844

ALSPAC

AF:

0.217

AC:

626

ESP6500AA

AF:

0.182

AC:

696

ESP6500EA

AF:

0.218

AC:

1465

ExAC

AF:

0.220

AC:

26648

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Duchenne muscular dystrophy

Benign:3

May 28, 2019

Mendelics

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 20, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The RefSeq base and residue are not consistent across bu ilds. The variant (c.7096C) represents the Alamut RefSeq base and minor allele. This allele (C) has been identified in 22% (1465/6727) of European American chro mosomes and 18% (696/3833) of African American chromosomes by the NHLBI Exome Se quencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1800275) and thus m eets criteria to be classified as benign. -

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

- -

Dilated cardiomyopathy 3B

Benign:1

Jul 30, 2021

Genome-Nilou Lab

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

0.13

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;.;T;.;.

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.65

T;T;.;T;T

MetaRNN

Benign

0.0033

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

2.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.40

N;.;N;.;N

REVEL

Benign

0.092

Sift

Benign

0.20

T;.;T;.;T

Sift4G

Benign

0.51

T;T;T;T;T

Polyphen

1.0

.;.;D;.;.

Vest4

0.54, 0.25, 0.55, 0.25

MPC

0.016

ClinPred

0.017

GERP RS

5.2

PromoterAI

-0.0046

Neutral

(source)

gMVP

0.22

Mutation Taster

=263/37

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.068

dbscSNV1_RF

Benign

0.50

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