chrX-32287676-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_004006.3(DMD):c.6143G>A(p.Ser2048Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000838 in 1,204,567 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 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. S2048I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000082 ( 0 hom. 33 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.56

Publications

0 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=0.05268076).

BP6

Variant X-32287676-C-T is Benign according to our data. Variant chrX-32287676-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 390847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 11 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.6143G>A	p.Ser2048Asn	missense_variant	Exon 43 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.6143G>A	p.Ser2048Asn	missense_variant	Exon 43 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.0000993

AC:

AN:

110739

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000969

Gnomad ASJ

AF:

0.00152

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000111

AC:

AN:

180766

AF XY:

0.0000914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00148

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000995

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000823

AC:

AN:

1093828

Hom.:

Cov.:

AF XY:

0.0000918

AC XY:

AN XY:

359474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26292

American (AMR)

AF:

0.0000285

AC:

AN:

35119

Ashkenazi Jewish (ASJ)

AF:

0.00186

AC:

AN:

19329

East Asian (EAS)

AF:

0.00

AC:

AN:

30099

South Asian (SAS)

AF:

0.00

AC:

AN:

53704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40369

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.0000536

AC:

AN:

838870

Other (OTH)

AF:

0.000174

AC:

AN:

45925

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.0000993

AC:

AN:

110739

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

33009

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30458

American (AMR)

AF:

0.0000969

AC:

AN:

10320

Ashkenazi Jewish (ASJ)

AF:

0.00152

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2603

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5795

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

52963

Other (OTH)

AF:

0.00

AC:

AN:

1489

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000478

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 17, 2016

GeneDx

Significance:Likely 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. -

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

Benign:1

Apr 24, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DMD: BP4, BS2 -

Cardiovascular phenotype

Benign:1

Jun 08, 2017

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 29, 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

0.087

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.23

.;T;.;.

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.65

T;.;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.053

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.6

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.74

.;N;.;N

REVEL

Benign

0.060

Sift

Benign

0.30

.;T;.;T

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.026

.;B;.;.

Vest4

0.19

MutPred

0.42

.;.;Loss of phosphorylation at S2048 (P = 0.0277);Loss of phosphorylation at S2048 (P = 0.0277);

MVP

0.36

MPC

0.016

ClinPred

0.013

GERP RS

3.2

gMVP

0.19

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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