Genetic Variant NM_004006.3:c.6322C>T (chrX-32217032-G-A) – ACMG Classification: Benign (-20 pts)

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.6322C>T(p.Arg2108Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,207,175 control chromosomes in the GnomAD database, including 25 homozygotes. There are 622 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2108H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0094 ( 13 hom., 278 hem., cov: 23)

Exomes 𝑓: 0.0011 ( 12 hom. 344 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.14

Publications

7 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065715313).

BP6

Variant X-32217032-G-A is Benign according to our data. Variant chrX-32217032-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00935 (1041/111330) while in subpopulation AFR AF = 0.0319 (979/30681). AF 95% confidence interval is 0.0302. There are 13 homozygotes in GnomAd4. There are 278 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 1041 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.6322C>T	p.Arg2108Cys	missense	Exon 44 of 79	NP_003997.2	P11532-1
DMD	NM_004009.3		c.6310C>T	p.Arg2104Cys	missense	Exon 44 of 79	NP_004000.1	P11532
DMD	NM_000109.4		c.6298C>T	p.Arg2100Cys	missense	Exon 44 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.6322C>T	p.Arg2108Cys	missense	Exon 44 of 79	ENSP00000354923.3	P11532-1
DMD	ENST00000378677.6	TSL:5	c.6310C>T	p.Arg2104Cys	missense	Exon 44 of 79	ENSP00000367948.2	P11532-11
DMD	ENST00000619831.5	TSL:5	c.2290C>T	p.Arg764Cys	missense	Exon 16 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes

AF:

0.00933

AC:

1038

AN:

111282

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00385

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00294

AC:

534

AN:

181372

AF XY:

0.00201

show subpopulations

Gnomad AFR exome

AF:

0.0366

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000727

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000744

Gnomad OTH exome

AF:

0.000672

GnomAD4 exome

AF:

0.00113

AC:

1237

AN:

1095845

Hom.:

Cov.:

AF XY:

0.000951

AC XY:

344

AN XY:

361675

show subpopulations

African (AFR)

AF:

0.0367

AC:

966

AN:

26322

American (AMR)

AF:

0.00214

AC:

AN:

35098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19328

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30137

South Asian (SAS)

AF:

0.000185

AC:

AN:

54025

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40446

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000773

AC:

AN:

840395

Other (OTH)

AF:

0.00250

AC:

115

AN:

45968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00935

AC:

1041

AN:

111330

Hom.:

Cov.:

AF XY:

0.00827

AC XY:

278

AN XY:

33618

show subpopulations

African (AFR)

AF:

0.0319

AC:

979

AN:

30681

American (AMR)

AF:

0.00384

AC:

AN:

10413

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.000371

AC:

AN:

2693

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5937

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000208

AC:

AN:

53012

Other (OTH)

AF:

0.00662

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

139

174

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:

0.00662

Hom.:

191

Bravo

AF:

0.0112

ESP6500AA

AF:

0.0326

AC:

125

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00309

AC:

375

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 3B (1)

Duchenne muscular dystrophy (1)

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

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.1

PhyloP100

2.1

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.12

Sift

Uncertain

0.018

Sift4G

Uncertain

0.0090

Polyphen

0.97

Vest4

0.16

MVP

0.40

MPC

0.018

ClinPred

0.025

GERP RS

5.8

gMVP

0.073

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over