X-32217062-G-A

Position:

• chrX-32217062-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004006.3(DMD):​c.6292C>T​(p.Arg2098*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,540 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.0003312
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.516

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-32217062-G-A is Pathogenic according to our data. Variant chrX-32217062-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32217062-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.6292C>T	p.Arg2098*	stop_gained, splice_region_variant	44/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.6292C>T	p.Arg2098*	stop_gained, splice_region_variant	44/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094540 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 360466

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duchenne muscular dystrophy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	This sequence change creates a premature translational stop signal (p.Arg2098*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (DMD) and X-linked dilated cardiomyopathy (PMID: 7951253, 9298822, 17041906, 19783145, 19937601, 23536893, 25612904). This variant is also known as C6500T. ClinVar contains an entry for this variant (Variation ID: 11260). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 16, 2022	PVS1, PM2, PP5 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 10, 2020

The DMD c.6292C>T, p.Arg2098ter variant (rs128626250) is reported in the literature in at least three individuals affected with Duchenne/Becker muscular dystrophy (Roberts 1994, Juan-Mateu 2012, Cho 2017) and has been reported to the ClinVar database as pathogenic (Variation ID: 11260). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Computational analysis also indicated that this variant may impact splicing by creating a cryptic donor splice site at the canonical acceptor site of intron 43 (Alamut v.2.11). Based on available information, this variant is considered to be pathogenic. References: Roberts et al. Searching for the 1 in 2,400,000: a review of dystrophin gene point mutations. Hum Mutat. 1994;4(1):1-11. Juan-Mateu et al. Isolated cardiomyopathy caused by a DMD nonsense mutation in somatic mosaicism: genetic normalization in skeletal muscle. Clin Genet. 2012 Dec;82(6):574-8 Cho et al. Consecutive analysis of mutation spectrum in the dystrophin gene of 507 Korean boys with Duchenne/Becker muscular dystrophy in a single center. Muscle Nerve. 2017 May;55(5):727-734 Gene statement: Pathogenic variants in DMD are inherited in an X-linked manner and are associated with Duchenne muscular dystrophy (MIM: 310200), Becker muscular dystrophy (MIM: 300376), and dilated cardiomyopathy (MIM: 302045). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.079	N
Vest4		0.77
GERP RS		-2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.40
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

Publications

LitVar

Other links and lift over

dbSNP: rs128626250; hg19: chrX-32235179; COSMIC: COSV63785966;