rs149322279

Variant names:

• chrX-31968382-G-A
• rs149322279
• NM_004006.3:c.6571C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_004006.3(DMD):​c.6571C>T​(p.Arg2191Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000223 in 1,208,397 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 95 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2191Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00022 (0 hom. 87 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 5.53
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08049196).
• BP6: Variant X-31968382-G-A is Benign according to our data. Variant chrX-31968382-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.6571C>T	p.Arg2191Trp	missense	Exon 45 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.6559C>T	p.Arg2187Trp	missense	Exon 45 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.6547C>T	p.Arg2183Trp	missense	Exon 45 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.6571C>T	p.Arg2191Trp	missense	Exon 45 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.6559C>T	p.Arg2187Trp	missense	Exon 45 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.2539C>T	p.Arg847Trp	missense	Exon 17 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.000216 AC: 24 AN: 111132 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000573

Gnomad ASJ AF: 0.00190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000378

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000227

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000388 AC: 71 AN: 182792 AF XY: 0.000415

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.000512

Gnomad ASJ exome AF: 0.00281

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000224 AC: 246 AN: 1097265 Hom.: 0 Cov.: 31 AF XY: 0.000240 AC XY: 87 AN XY: 363105

African (AFR) AF: 0.0000380 AC: 1 AN: 26338

American (AMR) AF: 0.000541 AC: 19 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 49 AN: 19337

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30192

South Asian (SAS) AF: 0.000259 AC: 14 AN: 54133

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4129

European-Non Finnish (NFE) AF: 0.000168 AC: 141 AN: 841442

Other (OTH) AF: 0.000413 AC: 19 AN: 46043

GnomAD4 genome AF: 0.000216 AC: 24 AN: 111132 Hom.: 0 Cov.: 23 AF XY: 0.000239 AC XY: 8 AN XY: 33454

African (AFR) AF: 0.00 AC: 0 AN: 30553

American (AMR) AF: 0.000573 AC: 6 AN: 10464

Ashkenazi Jewish (ASJ) AF: 0.00190 AC: 5 AN: 2629

East Asian (EAS) AF: 0.00 AC: 0 AN: 3521

South Asian (SAS) AF: 0.000378 AC: 1 AN: 2649

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5977

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000227 AC: 12 AN: 52923

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.000403 Hom.: 17

Bravo AF: 0.000370

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000874

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	6	not specified (6)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DMD-related disorder (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	Duchenne or Becker muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.49	T
PhyloP100		5.5
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.49
MVP		0.61
MPC		0.089
ClinPred		0.36	T
GERP RS		4.5
gMVP		0.61
Mutation Taster		=293/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149322279; hg19: chrX-31986499;