NM_004006.3:c.6463C>T

Variant names:

• chrX-31968490-G-A
• rs1800273
• NM_004006.3:c.6463C>T
• DMD p.Arg2155Trp

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.6463C>T​(p.Arg2155Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,208,510 control chromosomes in the GnomAD database, including 655 homozygotes. There are 14,143 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict 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. R2155Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.027 (40 hom., 851 hem., cov: 23)
  • Exomes 𝑓: 0.038 (615 hom. 13292 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 3.53
• Publications: 13 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: Orphanet, Ambry Genetics
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004711747).
• BP6: Variant X-31968490-G-A is Benign according to our data. Variant chrX-31968490-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.027 (3018/111649) while in subpopulation NFE AF = 0.0415 (2198/53004). AF 95% confidence interval is 0.04. There are 40 homozygotes in GnomAd4. There are 851 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3018 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.6463C>T	p.Arg2155Trp	missense	Exon 45 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.6451C>T	p.Arg2151Trp	missense	Exon 45 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.6439C>T	p.Arg2147Trp	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.6463C>T	p.Arg2155Trp	missense	Exon 45 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.6451C>T	p.Arg2151Trp	missense	Exon 45 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.2431C>T	p.Arg811Trp	missense	Exon 17 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 3020 AN: 111598 Hom.: 40 Cov.: 23

Gnomad AFR AF: 0.00573

Gnomad AMI AF: 0.0117

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000846

Gnomad SAS AF: 0.00592

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0212

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0261 AC: 4756 AN: 182171 AF XY: 0.0266

Gnomad AFR exome AF: 0.00579

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0274

GnomAD4 exome AF: 0.0377 AC: 41356 AN: 1096861 Hom.: 615 Cov.: 31 AF XY: 0.0366 AC XY: 13292 AN XY: 362857

African (AFR) AF: 0.00410 AC: 108 AN: 26326

American (AMR) AF: 0.0188 AC: 660 AN: 35075

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 352 AN: 19330

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30165

South Asian (SAS) AF: 0.00521 AC: 282 AN: 54118

European-Finnish (FIN) AF: 0.0321 AC: 1298 AN: 40476

Middle Eastern (MID) AF: 0.00775 AC: 32 AN: 4131

European-Non Finnish (NFE) AF: 0.0441 AC: 37110 AN: 841235

Other (OTH) AF: 0.0329 AC: 1513 AN: 46005

GnomAD4 genome AF: 0.0270 AC: 3018 AN: 111649 Hom.: 40 Cov.: 23 AF XY: 0.0251 AC XY: 851 AN XY: 33949

African (AFR) AF: 0.00571 AC: 176 AN: 30798

American (AMR) AF: 0.0321 AC: 337 AN: 10514

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 48 AN: 2640

East Asian (EAS) AF: 0.000849 AC: 3 AN: 3534

South Asian (SAS) AF: 0.00593 AC: 16 AN: 2696

European-Finnish (FIN) AF: 0.0297 AC: 180 AN: 6052

Middle Eastern (MID) AF: 0.0233 AC: 5 AN: 215

European-Non Finnish (NFE) AF: 0.0415 AC: 2198 AN: 53004

Other (OTH) AF: 0.0311 AC: 47 AN: 1513

Alfa AF: 0.0343 Hom.: 2217

Bravo AF: 0.0255

EpiCase AF: 0.0419

EpiControl AF: 0.0445

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	not provided (3)
-	-	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
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.96	T
PhyloP100		3.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Benign	0.18	T
Sift4G	Uncertain	0.0050	D
gMVP		0.25
Mutation Taster		=299/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1800273;

hg19: chrX-31986607;

COSMIC: COSV58925650;