Genetic Variant DMD:c.4233+2C>T (chrX-32411750-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2

The NM_004006.3(DMD):c.4233+2C>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000821 in 1,208,749 control chromosomes in the GnomAD database, including 1 homozygotes. There are 291 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., 21 hem., cov: 22)

Exomes 𝑓: 0.00084 ( 1 hom. 270 hem. )

Consequence

DMD
NM_004006.3 splice_donor, intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: 4.04

Publications

3 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 -7 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014650027 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: cagGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant X-32411750-G-A is Benign according to our data. Variant chrX-32411750-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94616.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000637 (71/111497) while in subpopulation AMR AF = 0.00182 (19/10454). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 71 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	Effect	Exon Rank	Protein	UniProt
DMD	NM_004006.3	MANE Select	c.4233+2C>T	splice_donor intron	N/A	NP_003997.2	P11532-1
DMD	NM_004009.3		c.4221+2C>T	splice_donor intron	N/A	NP_004000.1	P11532
DMD	NM_000109.4		c.4209+2C>T	splice_donor intron	N/A	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DMD	ENST00000357033.9	TSL:1 MANE Select	c.4233+2C>T	splice_donor intron	N/A	ENSP00000354923.3	P11532-1
DMD	ENST00000378677.6	TSL:5	c.4221+2C>T	splice_donor intron	N/A	ENSP00000367948.2	P11532-11
DMD	ENST00000619831.5	TSL:5	c.201+2C>T	splice_donor intron	N/A	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes

AF:

0.000637

AC:

AN:

111443

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00182

Gnomad ASJ

AF:

0.000377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000847

Gnomad OTH

AF:

0.000667

GnomAD2 exomes

AF:

0.000651

AC:

119

AN:

182827

AF XY:

0.000637

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000626

Gnomad NFE exome

AF:

0.000675

Gnomad OTH exome

AF:

0.000886

GnomAD4 exome

AF:

0.000839

AC:

921

AN:

1097252

Hom.:

Cov.:

AF XY:

0.000744

AC XY:

270

AN XY:

362738

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26375

American (AMR)

AF:

0.00199

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.000258

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30160

South Asian (SAS)

AF:

0.00

AC:

AN:

54128

European-Finnish (FIN)

AF:

0.0000741

AC:

AN:

40507

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.000953

AC:

802

AN:

841330

Other (OTH)

AF:

0.000803

AC:

AN:

46056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.000637

AC:

AN:

111497

Hom.:

Cov.:

AF XY:

0.000623

AC XY:

AN XY:

33711

show subpopulations

African (AFR)

AF:

0.000163

AC:

AN:

30744

American (AMR)

AF:

0.00182

AC:

AN:

10454

Ashkenazi Jewish (ASJ)

AF:

0.000377

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3514

South Asian (SAS)

AF:

0.00

AC:

AN:

2648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000847

AC:

AN:

53124

Other (OTH)

AF:

0.000659

AC:

AN:

1518

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:

0.000693

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000503

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Duchenne muscular dystrophy (3)

not specified (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 3B (1)

DMD-related disorder (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

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Benign

0.95

FATHMM_MKL

Benign

0.69

PhyloP100

4.0

GERP RS

3.7

PromoterAI

0.091

Neutral

(source)

Mutation Taster

=62/38

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