rs72468681

Variant names:

• chrX-32491508-A-C
• rs72468681
• NM_004006.3:c.2391T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-32491508-A-C
• chrX-32491508-A-G

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.2391T>G​(p.Asn797Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,208,031 control chromosomes in the GnomAD database, including 80 homozygotes. There are 4,378 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (2 hom., 221 hem., cov: 24)
  • Exomes 𝑓: 0.012 (78 hom. 4157 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.55
• Publications: 11 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

ENSG00000297605 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008066297).
• BP6: Variant X-32491508-A-C is Benign according to our data. Variant chrX-32491508-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94510.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 = 0.00695 (780/112178) while in subpopulation NFE AF = 0.0117 (622/53237). AF 95% confidence interval is 0.0109. There are 2 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 780 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.2391T>G	p.Asn797Lys	missense	Exon 20 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.2379T>G	p.Asn793Lys	missense	Exon 20 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.2367T>G	p.Asn789Lys	missense	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.2391T>G	p.Asn797Lys	missense	Exon 20 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.2379T>G	p.Asn793Lys	missense	Exon 20 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-126309T>G		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 782 AN: 112124 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.00185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.000277

Gnomad SAS AF: 0.00221

Gnomad FIN AF: 0.00721

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00794

GnomAD2 exomes AF: 0.00649 AC: 1158 AN: 178379 AF XY: 0.00652

Gnomad AFR exome AF: 0.00201

Gnomad AMR exome AF: 0.00184

Gnomad ASJ exome AF: 0.000809

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00700

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00698

GnomAD4 exome AF: 0.0119 AC: 13021 AN: 1095853 Hom.: 78 Cov.: 30 AF XY: 0.0115 AC XY: 4157 AN XY: 361375

African (AFR) AF: 0.00144 AC: 38 AN: 26352

American (AMR) AF: 0.00222 AC: 78 AN: 35125

Ashkenazi Jewish (ASJ) AF: 0.000671 AC: 13 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30148

South Asian (SAS) AF: 0.00351 AC: 189 AN: 53870

European-Finnish (FIN) AF: 0.00678 AC: 273 AN: 40263

Middle Eastern (MID) AF: 0.00389 AC: 16 AN: 4113

European-Non Finnish (NFE) AF: 0.0142 AC: 11966 AN: 840635

Other (OTH) AF: 0.00974 AC: 448 AN: 45984

GnomAD4 genome AF: 0.00695 AC: 780 AN: 112178 Hom.: 2 Cov.: 24 AF XY: 0.00644 AC XY: 221 AN XY: 34334

African (AFR) AF: 0.00185 AC: 57 AN: 30889

American (AMR) AF: 0.00313 AC: 33 AN: 10558

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3595

South Asian (SAS) AF: 0.00221 AC: 6 AN: 2709

European-Finnish (FIN) AF: 0.00721 AC: 44 AN: 6104

Middle Eastern (MID) AF: 0.0139 AC: 3 AN: 216

European-Non Finnish (NFE) AF: 0.0117 AC: 622 AN: 53237

Other (OTH) AF: 0.00784 AC: 12 AN: 1530

Alfa AF: 0.0101 Hom.: 171

Bravo AF: 0.00620

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0135 AC: 39

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.00832 AC: 56

ExAC AF: 0.00675 AC: 819

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)
-	-	2	Primary dilated cardiomyopathy (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.081
Sift	Benign	0.81	T
Sift4G	Benign	0.46	T
Polyphen		0.86	P
Vest4		0.34
MutPred		0.40		Gain of ubiquitination at N797 (P = 0.0138)
MVP		0.69
MPC		0.10
ClinPred		0.019	T
GERP RS		0.18
gMVP		0.078
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72468681; hg19: chrX-32509625; COSMIC: COSV63769803;