chrX-32699247-G-C

Variant names:

• chrX-32699247-G-C
• rs145668843
• NM_004006.3:c.696C>G

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.696C>G​(p.Ile232Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,207,499 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 132 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. I232L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00037 (0 hom. 128 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.51
• Publications: 5 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=0.24008453).
• BP6: Variant X-32699247-G-C is Benign according to our data. Variant chrX-32699247-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284717.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.696C>G	p.Ile232Met	missense	Exon 8 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.684C>G	p.Ile228Met	missense	Exon 8 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.672C>G	p.Ile224Met	missense	Exon 8 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.696C>G	p.Ile232Met	missense	Exon 8 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.672C>G	p.Ile224Met	missense	Exon 8 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.246+124048C>G		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.000215 AC: 24 AN: 111607 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000287

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.000668

GnomAD2 exomes AF: 0.000224 AC: 41 AN: 182849 AF XY: 0.000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00174

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000295

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000374 AC: 410 AN: 1095892 Hom.: 0 Cov.: 29 AF XY: 0.000354 AC XY: 128 AN XY: 361506

African (AFR) AF: 0.0000380 AC: 1 AN: 26331

American (AMR) AF: 0.0000853 AC: 3 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 24 AN: 19359

East Asian (EAS) AF: 0.00 AC: 0 AN: 30162

South Asian (SAS) AF: 0.00 AC: 0 AN: 54089

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.000430 AC: 361 AN: 840125

Other (OTH) AF: 0.000457 AC: 21 AN: 45994

GnomAD4 genome AF: 0.000215 AC: 24 AN: 111607 Hom.: 0 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33839

African (AFR) AF: 0.0000649 AC: 2 AN: 30812

American (AMR) AF: 0.000287 AC: 3 AN: 10462

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000283 AC: 15 AN: 53009

Other (OTH) AF: 0.000668 AC: 1 AN: 1498

Alfa AF: 0.000521 Hom.: 4

Bravo AF: 0.000257

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.54	D
PhyloP100		2.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.046	B
Vest4		0.64
MVP		0.94
MPC		0.021
ClinPred		0.060	T
GERP RS		2.8
gMVP		0.43
Mutation Taster		=96/4	polymorphism

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: rs145668843; hg19: chrX-32717364;