chrX-32217032-G-A

Variant names:

• chrX-32217032-G-A
• rs16990169
• NM_004006.3:c.6322C>T

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.6322C>T​(p.Arg2108Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,207,175 control chromosomes in the GnomAD database, including 25 homozygotes. There are 622 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 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. R2108H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (13 hom., 278 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (12 hom. 344 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.14
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065715313).
• BP6: Variant X-32217032-G-A is Benign according to our data. Variant chrX-32217032-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00935 (1041/111330) while in subpopulation AFR AF = 0.0319 (979/30681). AF 95% confidence interval is 0.0302. There are 13 homozygotes in GnomAd4. There are 278 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1041 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.6322C>T	p.Arg2108Cys	missense	Exon 44 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.6310C>T	p.Arg2104Cys	missense	Exon 44 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.6298C>T	p.Arg2100Cys	missense	Exon 44 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.6322C>T	p.Arg2108Cys	missense	Exon 44 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.6310C>T	p.Arg2104Cys	missense	Exon 44 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.2290C>T	p.Arg764Cys	missense	Exon 16 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1038 AN: 111282 Hom.: 13 Cov.: 23

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00385

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00294 AC: 534 AN: 181372 AF XY: 0.00201

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000727

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000744

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.00113 AC: 1237 AN: 1095845 Hom.: 12 Cov.: 29 AF XY: 0.000951 AC XY: 344 AN XY: 361675

African (AFR) AF: 0.0367 AC: 966 AN: 26322

American (AMR) AF: 0.00214 AC: 75 AN: 35098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19328

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30137

South Asian (SAS) AF: 0.000185 AC: 10 AN: 54025

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40446

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4126

European-Non Finnish (NFE) AF: 0.0000773 AC: 65 AN: 840395

Other (OTH) AF: 0.00250 AC: 115 AN: 45968

GnomAD4 genome AF: 0.00935 AC: 1041 AN: 111330 Hom.: 13 Cov.: 23 AF XY: 0.00827 AC XY: 278 AN XY: 33618

African (AFR) AF: 0.0319 AC: 979 AN: 30681

American (AMR) AF: 0.00384 AC: 40 AN: 10413

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.000371 AC: 1 AN: 2693

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5937

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

European-Non Finnish (NFE) AF: 0.000208 AC: 11 AN: 53012

Other (OTH) AF: 0.00662 AC: 10 AN: 1511

Alfa AF: 0.00662 Hom.: 191

Bravo AF: 0.0112

ESP6500AA AF: 0.0326 AC: 125

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00309 AC: 375

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	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	Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.1
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.16
MVP		0.40
MPC		0.018
ClinPred		0.025	T
GERP RS		5.8
gMVP		0.073
Mutation Taster		=100/0	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: rs16990169; hg19: chrX-32235149;