rs137898199

Variant summary

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

The NM_004006.3(DMD):c.5675G>A(p.Cys1892Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,207,834 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000020 ( 0 hom. 8 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.07

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=0.18473032).

BP6

Variant X-32343198-C-T is Benign according to our data. Variant chrX-32343198-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201751.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.5675G>A	p.Cys1892Tyr	missense_variant	40/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.5675G>A	p.Cys1892Tyr	missense_variant	40/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0000719

AC:

AN:

111242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33486

show subpopulations

Gnomad AFR

AF:

0.000229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000379

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

183006

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

67650

show subpopulations

Gnomad AFR exome

AF:

0.000304

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:

0.0000201

AC:

AN:

1096537

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

362033

show subpopulations

Gnomad4 AFR exome

AF:

0.000455

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:

0.00000238

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.0000719

AC:

AN:

111297

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33551

show subpopulations

Gnomad4 AFR

AF:

0.000228

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000380

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000340

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 03, 2015

p.Cys1892Tyr (TGC>TAC): c.5675 G>A in exon 40 of the DMD gene (NM_004006.2). A variant of unknown significance has been identified in the DMD gene. The C1892Y variant has not been published as a mutation or as a benign polymorphism to our knowledge. The C1892Y variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The C1892Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, no missense mutations in nearby residues have been reported in association with DMD-related disorders, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). -

Dystrophin deficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2023

The p.C1892Y variant (also known as c.5675G>A), located in coding exon 40 of the DMD gene, results from a G to A substitution at nucleotide position 5675. The cysteine at codon 1892 is replaced by tyrosine, an amino acid with highly dissimilar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.003% (6/204748) total alleles studied, including two hemizygotes. The highest observed frequency was 0.03% (6/18990) of African alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.38

Cadd

Benign

Dann

Benign

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;.;D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.78

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.88

.;P;.;.;.

Vest4

0.59

MVP

0.52

MPC

0.058

ClinPred

0.13

GERP RS

6.1

gMVP

0.25

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