rs1060502649

Variant names:

• chrX-31679421-C-T
• rs1060502649
• NM_004006.3:c.7826G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004006.3(DMD):​c.7826G>A​(p.Gly2609Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,368 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.42
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14190465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.7826G>A	p.Gly2609Asp	missense_variant	Exon 53 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.7826G>A	p.Gly2609Asp	missense_variant	Exon 53 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097368 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362816

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 54033

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841699

Other (OTH) AF: 0.00 AC: 0 AN: 46057

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 06, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Gly2609Asp (c.7826G>A) in exon 53 of the DMD gene (NM_004006.2) Chromosome position X:31697538 C / T Given the lack of case data, and this variant's absence in the broader population, we classify it as being of unknown significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in family members. The DMD gene is associated with X-linked Duchenne Muscular Dystrophy (DMD) (MedGen UID:3925), Becker Muscular Dystrophy (BMD) (MedGen UID: 182959) and dilated cardiomyopathy (DCM) (MedGen UID: 472068). This is a completely novel variant. It has not been reported in the literature in association with disease, and it not present in population databases. Invitae reports that this variant is possibly mosaic in our patient, who has early-onset atrial fibrillation. It had not been reported to ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) by any lab as of 4/4/2017. This is a nonconservative amino acid change that replaces a nonpolar glycine with a negatively-charged aspartic acid. The glycine residue is not conserved across vertebrate species, and is frequently replaced with another nonpolar amino acid such as alanine or isoleucine. Of note, the default amino acid is aspartic acid in brush-tailed rat. No missense variants within 10 amino acids to either side are currently listed in ClinVar as Likely Pathogenic or Pathogenic. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT,PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is good sequencing coverage at this site. 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. The curators made an effort to exclude individuals with severe pediatric diseases. -

Duchenne muscular dystrophy Uncertain:1

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2609 of the DMD protein (p.Gly2609Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 409927). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DMD protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	.;T;T;.;.;T;.;.;T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D;.;.;.;D;.;D;D;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		3.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.16	N;N;N;N;.;N;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.16	T;T;T;T;.;D;.;T;T
Sift4G	Benign	0.075	T;T;T;T;D;D;D;D;T
Polyphen		0.21, 0.90, 0.25, 0.71	.;B;P;B;.;P;.;.;B
Vest4		0.17, 0.17, 0.17, 0.27, 0.20, 0.26, 0.20
MutPred		0.52		.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0573);.;
MVP		0.31
MPC		0.020
ClinPred		0.23	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.56
Mutation Taster		=84/16	polymorphism

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: rs1060502649; hg19: chrX-31697538;