rs72468679

Variant names:

• chrX-32491409-G-A
• rs72468679
• NM_004006.3:c.2490C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-32491409-G-A
• chrX-32491409-G-C
• chrX-32491409-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_004006.3(DMD):​c.2490C>T​(p.Asn830Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,209,995 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 185 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 0.00041 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00049 (0 hom. 176 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 3.38
• Publications: 2 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

ENSG00000297605 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-32491409-G-A is Benign according to our data. Variant chrX-32491409-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94516.
• BP7: Synonymous conserved (PhyloP=3.38 with no splicing effect.
• BS2: High AC in GnomAd4 at 46 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.2490C>T	p.Asn830Asn	synonymous	Exon 20 of 79	NP_003997.2
	DMD	NM_004009.3		c.2478C>T	p.Asn826Asn	synonymous	Exon 20 of 79	NP_004000.1
	DMD	NM_000109.4		c.2466C>T	p.Asn822Asn	synonymous	Exon 20 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.2490C>T	p.Asn830Asn	synonymous	Exon 20 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.2478C>T	p.Asn826Asn	synonymous	Exon 20 of 79	ENSP00000367948.2
	DMD	ENST00000420596.5	TSL:5	c.94-126210C>T		intron	N/A	ENSP00000399897.1

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 47 AN: 111923 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000770

Gnomad OTH AF: 0.000665

GnomAD2 exomes AF: 0.000463 AC: 85 AN: 183418 AF XY: 0.000575

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000867

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.000494 AC: 542 AN: 1098021 Hom.: 0 Cov.: 30 AF XY: 0.000484 AC XY: 176 AN XY: 363381

African (AFR) AF: 0.0000758 AC: 2 AN: 26401

American (AMR) AF: 0.0000568 AC: 2 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54138

European-Finnish (FIN) AF: 0.0000987 AC: 4 AN: 40508

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4135

European-Non Finnish (NFE) AF: 0.000595 AC: 501 AN: 841960

Other (OTH) AF: 0.000325 AC: 15 AN: 46090

GnomAD4 genome AF: 0.000411 AC: 46 AN: 111974 Hom.: 0 Cov.: 23 AF XY: 0.000263 AC XY: 9 AN XY: 34156

African (AFR) AF: 0.0000974 AC: 3 AN: 30796

American (AMR) AF: 0.0000950 AC: 1 AN: 10524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000770 AC: 41 AN: 53261

Other (OTH) AF: 0.000657 AC: 1 AN: 1521

Alfa AF: 0.000400 Hom.: 3

Bravo AF: 0.000329

EpiCase AF: 0.00104

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.5
DANN	Benign	0.71
PhyloP100		3.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72468679; hg19: chrX-32509526;