rs16990169

chrX-32217032-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):c.6322C>T(p.Arg2108Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,207,175 control chromosomes in the GnomAD database, including 25 homozygotes. There are 622 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2108H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (13 hom., 278 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (12 hom. 344 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.14

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065715313).
• BP6: Variant X-32217032-G-A is Benign according to our data. Variant chrX-32217032-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32217032-G-A is described in Lovd as [Likely_benign]. Variant chrX-32217032-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00935 (1041/111330) while in subpopulation AFR AF= 0.0319 (979/30681). AF 95% confidence interval is 0.0302. There are 13 homozygotes in gnomad4. There are 278 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.6322C>T	p.Arg2108Cys	missense_variant	44/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.6322C>T	p.Arg2108Cys	missense_variant	44/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1038 AN: 111282 Hom.: 13 Cov.: 23 AF XY: 0.00819 AC XY: 275 AN XY: 33560

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00385

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00294 AC: 534 AN: 181372 Hom.: 4 AF XY: 0.00201 AC XY: 133 AN XY: 66322

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000727

Gnomad SAS exome AF: 0.000159

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000744

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.00113 AC: 1237 AN: 1095845 Hom.: 12 Cov.: 29 AF XY: 0.000951 AC XY: 344 AN XY: 361675

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.00214

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000773

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00935 AC: 1041 AN: 111330 Hom.: 13 Cov.: 23 AF XY: 0.00827 AC XY: 278 AN XY: 33618

Gnomad4 AFR AF: 0.0319

Gnomad4 AMR AF: 0.00384

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000208

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00341 Hom.: 39

Bravo AF: 0.0112

ESP6500AA AF: 0.0326 AC: 125

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00309 AC: 375

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2021	Variant summary: DMD c.6322C>T (p.Arg2108Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 181372 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 267 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.6322C>T in individuals affected with Dystrophinopathies and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Arg2108Cys in exon 44 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 3.3% (125/3833) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs16990169). -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 20, 2017

- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 21, 2022

- -

Dilated cardiomyopathy 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 02, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Duchenne muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Uncertain	24
Dann	Pathogenic	1.0
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.94	D;.;D;D
MetaRNN	Benign	0.0066	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.97	.;D;.;.
Vest4		0.16
MVP		0.40
MPC		0.018
ClinPred		0.025	T
GERP RS		5.8
gMVP		0.073

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

Publications

LitVar

Other links and lift over

dbSNP: rs16990169; hg19: chrX-32235149;