NM_004006.3:c.2096C>G

Variant names:

• chrX-32545231-G-C
• rs202008454
• NM_004006.3:c.2096C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004006.3(DMD):​c.2096C>G​(p.Ala699Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000168 in 1,208,596 control chromosomes in the GnomAD database, including 2 homozygotes. There are 77 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A699T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (2 hom. 69 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 5.73
• Publications: 4 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006035477).
• BP6: Variant X-32545231-G-C is Benign according to our data. Variant chrX-32545231-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194741.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000215 (24/111818) while in subpopulation EAS AF = 0.00649 (23/3543). AF 95% confidence interval is 0.00444. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 24 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.2096C>G	p.Ala699Gly	missense	Exon 17 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.2084C>G	p.Ala695Gly	missense	Exon 17 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.2072C>G	p.Ala691Gly	missense	Exon 17 of 79	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.2096C>G	p.Ala699Gly	missense	Exon 17 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.2072C>G	p.Ala691Gly	missense	Exon 17 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.2084C>G	p.Ala695Gly	missense	Exon 17 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.000215 AC: 24 AN: 111767 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00647

Gnomad SAS AF: 0.000372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000639 AC: 117 AN: 183136 AF XY: 0.000606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00773

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000163 AC: 179 AN: 1096778 Hom.: 2 Cov.: 31 AF XY: 0.000190 AC XY: 69 AN XY: 362296

African (AFR) AF: 0.00 AC: 0 AN: 26363

American (AMR) AF: 0.00 AC: 0 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19364

East Asian (EAS) AF: 0.00480 AC: 145 AN: 30190

South Asian (SAS) AF: 0.000388 AC: 21 AN: 54107

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840907

Other (OTH) AF: 0.000261 AC: 12 AN: 46048

GnomAD4 genome AF: 0.000215 AC: 24 AN: 111818 Hom.: 0 Cov.: 23 AF XY: 0.000235 AC XY: 8 AN XY: 34034

African (AFR) AF: 0.00 AC: 0 AN: 30805

American (AMR) AF: 0.00 AC: 0 AN: 10498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00649 AC: 23 AN: 3543

South Asian (SAS) AF: 0.000374 AC: 1 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6083

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53130

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.000174 Hom.: 2

Bravo AF: 0.000366

ExAC AF: 0.000585 AC: 71

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 3B (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.45	T
PhyloP100		5.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.13
Sift	Benign	0.054	T
Sift4G	Uncertain	0.021	D
Polyphen		0.0010	B
Vest4		0.14
MVP		0.79
MPC		0.016
ClinPred		0.070	T
GERP RS		3.8
gMVP		0.15
Mutation Taster		=96/4	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: rs202008454; hg19: chrX-32563348; COSMIC: COSV55860968;