X-31968382-G-A

Position:

chrX-31968382-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004006.3(DMD):c.6571C>T(p.Arg2191Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000223 in 1,208,397 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 95 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00022 ( 0 hom. 87 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: 5.53

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08049196).

BP6

Variant X-31968382-G-A is Benign according to our data. Variant chrX-31968382-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197522.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=6, Uncertain_significance=1}. Variant chrX-31968382-G-A is described in Lovd as [Benign]. Variant chrX-31968382-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.6571C>T	p.Arg2191Trp	missense_variant	45/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.6571C>T	p.Arg2191Trp	missense_variant	45/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.000216

AC:

AN:

111132

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

33454

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000573

Gnomad ASJ

AF:

0.00190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000378

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000227

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000388

AC:

AN:

182792

Hom.:

AF XY:

0.000415

AC XY:

AN XY:

67526

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.000512

Gnomad ASJ exome

AF:

0.00281

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000315

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000319

Gnomad OTH exome

AF:

0.000665

GnomAD4 exome

AF:

0.000224

AC:

246

AN:

1097265

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

AN XY:

363105

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.000541

Gnomad4 ASJ exome

AF:

0.00253

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000259

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000168

Gnomad4 OTH exome

AF:

0.000413

GnomAD4 genome

AF:

0.000216

AC:

AN:

111132

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

33454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000573

Gnomad4 ASJ

AF:

0.00190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000378

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000227

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000429

Hom.:

Bravo

AF:

0.000370

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.000874

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2019	This variant is associated with the following publications: (PMID: 10573008, 7599634, 7849724, 11710958) -
Likely benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 08, 2017	p.Arg2191Trp (c.6571C>T) in exon 45 of the DMD gene (NM_004006.2; ChrXg.31986499G>A) SCICD Classification: likely benign based on relatively high frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: DMD encodes dystrophin, an integral skeletal muscle protein. Hemizygous pathogenic variants in DMD are the cause Duchenne and Becker muscular dystrophies. DMD is located on the X chromosome and thus males are most severely affected. The first signs are muscle weakness, and is often the major health issue for patients with DMD and BMD; however, males often pass away from heart failure and related complications. Importantly, carrier females can manifest symptoms associated with pathogenic variants in the DMD gene, most typically as dilated cardiomyopathy. About 20% of female carriers have EKG abnormalities. Female carriers can also have muscle weakness; however, this is rare. Loss of function variants in DMD are usually sufficient to cause disease. Case data (not including our patient): WEAK: this variant is present in at least 7 individuals referred for genetic testing; however, clinical phenotype is not clear. ClinVar: Invitae, GeneDx, EGL Genetic Diagnostics and the University of Chicago have submitted this variant to ClinVar, classified as either benign or likely benign. number of patients, evidence. Cases in the literature: Nigro et al (1994) reported this variant in one patient with Duchenne muscular dystropy. This variant is presumed de novo (not present in mother). Kneppers et al (1995) reported this variant in 1 of 70 patients with Duchenne/Becker Muscular dystrophy. They determined that this variant was not likely to be causative of DMD based on population data they had at the time. Bennett et al (2001) reported this variant in one patient with Duchenne muscular dystrophy. This patient had other variants that could have been causative of disease. Segregation data: none reported In silico data (missense variants only): Per the test report, "Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. " Conservation data: The arginine at codon 2191 is completely conserved across species. Neighboring amino acids are not completely conserved. Nearby pathogenic variants at this codon or neighboring codons: none Population data: Highest MAF in the Ashkenazi Jewish population: 0.26%%. The variant was reported online in 68 of 178,054 chromosomes in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 19 of 7,276 chromosomes of Ashkenazi Jewish descent (MAF=0.26%), 15 of 26,479 chromosomes of Latino descent, 25 of 79,602 chromosomes of European descent, 6 of 19,141 chromosomes of South Asian descent, 1 of 12,223 chromosomes of African descent and 2 of 4,039 chromosomes of "other" descent. This variant was present in 28 males. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DMD: BP4, BS2 -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 29, 2018	The p.Arg2191Trp variant in DMD is classified as likely benign because it has be en identified in 0.03% (9/47899) of European chromosomes, including 14 hemizygot es, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ; dbSNP rs149322279). It has also been reported in 3 individuals with clinical features of Duchenne Muscular Dystrophy, one of whom carried another pathogenic variant sufficient to cause disease (Nigro 1994, Kneppers 1995, Bennett 2001). ACMG/AMP Criteria applied: BS1, BP1, BP2. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2019	Variant summary: DMD c.6571C>T (p.Arg2191Trp) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 182792 control chromosomes including 28 hemizygotes. The observed variant frequency is approximately 35-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is benign. Co-occurrences with other pathogenic variant(s) have been reported (DMD c.2665C>T, p.Arg889X), providing supporting evidence for a benign role. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant six times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Primary familial dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 21, 2019

- -

DMD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2017

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

.;D;.;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;.;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.080

T;T;T;T

MetaSVM

Benign

-0.49

MutationTaster

Benign

0.97

D;D;D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-4.4

.;D;.;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

.;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.99

.;D;.;.

Vest4

0.49

MVP

0.61

MPC

0.089

ClinPred

0.36

GERP RS

4.5

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over