rs72468630

Variant names:

• chrX-32362950-C-G
• rs72468630
• NM_004006.3:c.5163G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-32362950-C-G
• chrX-32362950-C-A

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.5163G>C​(p.Lys1721Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,206,361 control chromosomes in the GnomAD database, including 1 homozygotes. There are 143 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. K1721M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., 15 hem., cov: 22)
  • Exomes 𝑓: 0.00030 (1 hom. 128 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.99
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008870751).
• BP6: Variant X-32362950-C-G is Benign according to our data. Variant chrX-32362950-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 455905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000288 (32/110956) while in subpopulation EAS AF = 0.00826 (29/3509). AF 95% confidence interval is 0.00591. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 32 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.5163G>C	p.Lys1721Asn	missense	Exon 37 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.5151G>C	p.Lys1717Asn	missense	Exon 37 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.5139G>C	p.Lys1713Asn	missense	Exon 37 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.5163G>C	p.Lys1721Asn	missense	Exon 37 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.5151G>C	p.Lys1717Asn	missense	Exon 37 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.1131G>C	p.Lys377Asn	missense	Exon 9 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 32 AN: 110899 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00824

Gnomad SAS AF: 0.000754

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00108 AC: 191 AN: 177459 AF XY: 0.00110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.000454

GnomAD4 exome AF: 0.000302 AC: 331 AN: 1095405 Hom.: 1 Cov.: 31 AF XY: 0.000355 AC XY: 128 AN XY: 360953

African (AFR) AF: 0.00 AC: 0 AN: 26376

American (AMR) AF: 0.00 AC: 0 AN: 34939

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19348

East Asian (EAS) AF: 0.00820 AC: 247 AN: 30138

South Asian (SAS) AF: 0.000873 AC: 47 AN: 53836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40423

Middle Eastern (MID) AF: 0.000970 AC: 4 AN: 4122

European-Non Finnish (NFE) AF: 0.0000167 AC: 14 AN: 840231

Other (OTH) AF: 0.000413 AC: 19 AN: 45992

GnomAD4 genome AF: 0.000288 AC: 32 AN: 110956 Hom.: 0 Cov.: 22 AF XY: 0.000452 AC XY: 15 AN XY: 33184

African (AFR) AF: 0.00 AC: 0 AN: 30516

American (AMR) AF: 0.00 AC: 0 AN: 10354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00826 AC: 29 AN: 3509

South Asian (SAS) AF: 0.000756 AC: 2 AN: 2646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5873

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53027

Other (OTH) AF: 0.00 AC: 0 AN: 1493

Alfa AF: 0.000364 Hom.: 4

Bravo AF: 0.000631

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00103 AC: 125

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.78	T
PhyloP100		3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.49
MutPred		0.52		Loss of ubiquitination at K1721 (P = 0.0134)
MVP		0.73
MPC		0.056
ClinPred		0.044	T
GERP RS		5.2
gMVP		0.31
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: rs72468630; hg19: chrX-32381067; COSMIC: COSV63764852;