X-32485077-T-C

Variant names:

• chrX-32485077-T-C
• rs228406
• NM_004006.3:c.2645A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_004006.3(DMD):​c.2645A>G​(p.Asp882Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D882V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.68 (18016 hom., 22248 hem., cov: 23)
  • Exomes 𝑓: 0.68 (171444 hom. 248464 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.937
• Publications: 44 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8961167E-5).
• BP6: Variant X-32485077-T-C is Benign according to our data. Variant chrX-32485077-T-C is described in ClinVar as Benign. ClinVar VariationId is 166842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.2645A>G	p.Asp882Gly	missense_variant	Exon 21 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.2645A>G	p.Asp882Gly	missense_variant	Exon 21 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.679 AC: 74818 AN: 110201 Hom.: 18029 Cov.: 23

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.687

GnomAD2 exomes AF: 0.728 AC: 133392 AN: 183171 AF XY: 0.724

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.854

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.886

Gnomad FIN exome AF: 0.812

Gnomad NFE exome AF: 0.660

Gnomad OTH exome AF: 0.699

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.682 AC: 748068 AN: 1097332 Hom.: 171444 Cov.: 39 AF XY: 0.684 AC XY: 248464 AN XY: 363044

African (AFR) AF: 0.626 AC: 16505 AN: 26382

American (AMR) AF: 0.844 AC: 29718 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 11932 AN: 19371

East Asian (EAS) AF: 0.854 AC: 25794 AN: 30187

South Asian (SAS) AF: 0.780 AC: 42241 AN: 54124

European-Finnish (FIN) AF: 0.805 AC: 32603 AN: 40514

Middle Eastern (MID) AF: 0.689 AC: 2848 AN: 4133

European-Non Finnish (NFE) AF: 0.659 AC: 554816 AN: 841369

Other (OTH) AF: 0.686 AC: 31611 AN: 46051

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.679 AC: 74834 AN: 110252 Hom.: 18016 Cov.: 23 AF XY: 0.684 AC XY: 22248 AN XY: 32514

African (AFR) AF: 0.630 AC: 19115 AN: 30334

American (AMR) AF: 0.765 AC: 7878 AN: 10301

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 1617 AN: 2629

East Asian (EAS) AF: 0.875 AC: 3036 AN: 3471

South Asian (SAS) AF: 0.789 AC: 2025 AN: 2567

European-Finnish (FIN) AF: 0.813 AC: 4699 AN: 5778

Middle Eastern (MID) AF: 0.651 AC: 142 AN: 218

European-Non Finnish (NFE) AF: 0.661 AC: 34914 AN: 52792

Other (OTH) AF: 0.679 AC: 1019 AN: 1500

Alfa AF: 0.660 Hom.: 102412

Bravo AF: 0.679

TwinsUK AF: 0.664 AC: 2463

ALSPAC AF: 0.652 AC: 1883

ESP6500AA AF: 0.628 AC: 2407

ESP6500EA AF: 0.663 AC: 4460

ExAC AF: 0.719 AC: 87334

EpiCase AF: 0.659

EpiControl AF: 0.654

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a RefSeq error. The reference base (c.2645A) is the minor allele. This a llele (A) has been identified in 34% (2268/6728) of European American chromosome s and 37% (1426/3833) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs228406) and thus meets c riteria to be classified as benign. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 04, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30342905, 29604111) -

Duchenne muscular dystrophy Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1

Apr 20, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 3B Benign:1

Jul 30, 2021

Genome-Nilou Lab

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	0.068
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	15
DANN	Benign	0.80
DEOGEN2	Benign	0.20	.;T;.;.
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.015	T;.;T;T
MetaRNN	Benign	0.000019	T;T;T;T
MetaSVM	Benign	-0.98	T
PhyloP100		0.94
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.45	.;N;.;N
REVEL	Benign	0.022
Sift	Benign	0.52	.;T;.;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.056
MPC		0.016
ClinPred		0.0016	T
GERP RS		3.1
gMVP		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs228406; hg19: chrX-32503194; COSMIC: COSV63760235;