rs372600090

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_004006.3(DMD):c.8212T>C(p.Trp2738Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,209,545 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 0 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 9.10

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 Likely_benign. Variant got -5 ACMG points.

BP6

Variant X-31627678-A-G is Benign according to our data. Variant chrX-31627678-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264464.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.8212T>C	p.Trp2738Arg	missense_variant	Exon 55 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.8212T>C	p.Trp2738Arg	missense_variant	Exon 55 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

112196

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34360

show subpopulations

Gnomad AFR

AF:

0.000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000276

AC:

AN:

181388

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

66582

show subpopulations

Gnomad AFR exome

AF:

0.000383

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097349

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362877

show subpopulations

Gnomad4 AFR exome

AF:

0.000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000134

AC:

AN:

112196

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34360

show subpopulations

Gnomad4 AFR

AF:

0.000485

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 30, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Mar 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W2738R variant (also known as c.8212T>C), located in coding exon 55 of the DMD gene, results from a T to C substitution at nucleotide position 8212. The tryptophan at codon 2738 is replaced by arginine, an amino acid with dissimilar properties. Based on data from gnomAD, the C allele has an overall frequency of 0.003% (7/203495) total alleles studied, including 2 hemizygotes. The highest observed frequency was 0.04% (7/19008) of African alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Dec 06, 2017

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

Benign:1

Oct 24, 2024

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

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;T;T;.;.;T;.;.;T

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

D;.;.;.;D;.;D;D;.

M_CAP

Pathogenic

0.48

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.70

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.9

D;N;D;N;.;D;.;D;N

REVEL

Uncertain

0.47

Sift

Benign

0.047

D;T;T;T;.;D;.;D;T

Sift4G

Benign

0.13

T;T;T;T;T;T;T;T;T

Polyphen

0.72, 1.0, 0.64

.;P;D;P;.;D;.;.;P

Vest4

0.87, 0.89, 0.87, 0.83, 0.88, 0.83, 0.85, 0.87

MutPred

0.58

.;.;.;.;.;.;.;Gain of disorder (P = 0.0016);.;

MVP

0.86

MPC

0.088

ClinPred

0.45

GERP RS

5.8

gMVP

0.74

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

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