X-154381042-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000117.3(EMD):c.610C>T(p.Arg204Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,210,803 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000014 ( 0 hom. 1 hem. )

Consequence

EMD
NM_000117.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.09

Publications

1 publications found

Variant links:

Genes affected

EMD (HGNC:3331): (emerin) Emerin is a serine-rich nuclear membrane protein and a member of the nuclear lamina-associated protein family. It mediates membrane anchorage to the cytoskeleton. Dreifuss-Emery muscular dystrophy is an X-linked inherited degenerative myopathy resulting from mutation in the emerin gene. [provided by RefSeq, Jul 2008]

EMD Gene-Disease associations (from GenCC):

X-linked Emery-Dreifuss muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
heart conduction disease
Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp

EMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21084535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3 link	c.610C>T	p.Arg204Cys	missense_variant	Exon 6 of 6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9 link	c.610C>T	p.Arg204Cys	missense_variant	Exon 6 of 6	1	NM_000117.3	ENSP00000358857.4

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112733

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000218

AC:

AN:

183163

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1098070

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000142

AC:

AN:

842133

Other (OTH)

AF:

0.0000217

AC:

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112733

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34881

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31016

American (AMR)

AF:

0.00

AC:

AN:

10746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3605

South Asian (SAS)

AF:

0.00

AC:

AN:

2757

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6277

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53237

Other (OTH)

AF:

0.00

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Emery-Dreifuss muscular dystrophy 1, X-linked

Uncertain:1

Jul 13, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 10, 2012

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg204Cys c.610 CGT>TGT in exon 6 of the EMD gene (NM_000117.2): The Arg204Cys variant in the EMD gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Server reports Arg204Cys was not observed in approximately 6,300 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Arg204Cys results in a semi-conservative amino acid substitution of a positively charged Arginine residue with a neutral, polar Cystein residue, which might affect disulfide bonds. In silico analysis predicts Arg204Cys is probably damaging to the protein structure/function. Nevertheless, the Arg204 residue is not well conserved, as a Cysteine residue is present at this position in horse. Also, no missense mutations in nearby codons have been reported in association with EDMD. With the clinical and molecular information available at this time, we cannot definitively determine if Arg204Cys is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). -

X-linked Emery-Dreifuss muscular dystrophy

Uncertain:1

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 204 of the EMD protein (p.Arg204Cys). This variant is present in population databases (rs782299893, gnomAD 0.005%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with EMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 201776). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EMD protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Nov 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R204C variant (also known as c.610C>T), located in coding exon 6 of the EMD gene, results from a C to T substitution at nucleotide position 610. The arginine at codon 204 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on data from gnomAD, the T allele has an overall frequency of 0.0024% (5/205035) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0187% (1/5339) of Other alleles. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;T

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.2

L;.

PhyloP100

1.1

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.19

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.029

B;.

Vest4

0.30

MutPred

0.53

Loss of MoRF binding (P = 0.0085);.;

MVP

0.77

MPC

0.38

ClinPred

0.19

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.60

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over