X-32217062-G-C

Variant names:

• chrX-32217062-G-C
• rs128626250
• NM_004006.3:c.6292C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004006.3(DMD):​c.6292C>G​(p.Arg2098Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,542 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2098Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense, splice_region
• Scores: Splicing: ADA: 0.00007089
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.516
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2356573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.6292C>G	p.Arg2098Gly	missense_variant, splice_region_variant	Exon 44 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.6292C>G	p.Arg2098Gly	missense_variant, splice_region_variant	Exon 44 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094542 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 360468

African (AFR) AF: 0.00 AC: 0 AN: 26295

American (AMR) AF: 0.00 AC: 0 AN: 35093

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19316

East Asian (EAS) AF: 0.00 AC: 0 AN: 30118

South Asian (SAS) AF: 0.00 AC: 0 AN: 53985

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839257

Other (OTH) AF: 0.00 AC: 0 AN: 45917

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;.;.
LIST_S2	Benign	0.84	T;.;T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	.;.;.;.
PhyloP100		0.52
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.0	.;N;.;N
Sift	Pathogenic	0.0	.;D;.;D
Sift4G	Benign	0.068	T;T;T;T
Vest4		0.31
ClinPred		0.65	D
GERP RS		-2.7
gMVP		0.21
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.022
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: rs128626250; hg19: chrX-32235179;