rs199986217

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_004006.3(DMD):c.2827C>T(p.Arg943Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,208,551 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 hemizygotes in GnomAD. 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. R943S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00019 ( 0 hom. 63 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 9.33

Publications

5 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-32472286-G-A is Benign according to our data. Variant chrX-32472286-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94539.

BS2

High AC in GnomAd4 at 24 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMD	NM_004006.3	MANE Select	c.2827C>T	p.Arg943Cys	missense	Exon 22 of 79	NP_003997.2	P11532-1
DMD	NM_004009.3		c.2815C>T	p.Arg939Cys	missense	Exon 22 of 79	NP_004000.1	P11532
DMD	NM_000109.4		c.2803C>T	p.Arg935Cys	missense	Exon 22 of 79	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMD	ENST00000357033.9	TSL:1 MANE Select	c.2827C>T	p.Arg943Cys	missense	Exon 22 of 79	ENSP00000354923.3	P11532-1
DMD	ENST00000378677.6	TSL:5	c.2815C>T	p.Arg939Cys	missense	Exon 22 of 79	ENSP00000367948.2	P11532-11
DMD	ENST00000420596.5	TSL:5	c.94-107087C>T		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes

AF:

0.000216

AC:

AN:

111242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000192

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000377

Gnomad OTH

AF:

0.000674

GnomAD2 exomes

AF:

0.000191

AC:

AN:

182873

AF XY:

0.000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000185

AC:

203

AN:

1097253

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

362727

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26371

American (AMR)

AF:

0.0000853

AC:

AN:

35165

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19366

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30174

South Asian (SAS)

AF:

0.000166

AC:

AN:

54098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40451

Middle Eastern (MID)

AF:

0.000968

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.000210

AC:

177

AN:

841447

Other (OTH)

AF:

0.000174

AC:

AN:

46050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.000216

AC:

AN:

111298

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33524

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30586

American (AMR)

AF:

0.000192

AC:

AN:

10418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3544

South Asian (SAS)

AF:

0.00

AC:

AN:

2630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000377

AC:

AN:

53086

Other (OTH)

AF:

0.000666

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.000416

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000206

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Duchenne muscular dystrophy (2)

not specified (2)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 3B (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.73

PhyloP100

9.3

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.30

Sift

Uncertain

0.014

Sift4G

Uncertain

0.016

Polyphen

0.96

Vest4

0.58

MVP

0.60

MPC

0.13

ClinPred

0.23

GERP RS

5.0

gMVP

0.20

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: -9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over