rs61749711

Positions:

chrX-154031246-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001110792.2(MECP2):c.618C>T(p.Ser206=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,209,931 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,176 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., 59 hem., cov: 23)

Exomes 𝑓: 0.0032 ( 4 hom. 1117 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0860

Variant links:

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008058667).

BP6

Variant X-154031246-G-A is Benign according to our data. Variant chrX-154031246-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031246-G-A is described in Lovd as [Likely_benign]. Variant chrX-154031246-G-A is described in Lovd as [Benign]. Variant chrX-154031246-G-A is described in Lovd as [Pathogenic].

BP7

Synonymous conserved (PhyloP=-0.086 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00195 (218/111719) while in subpopulation NFE AF= 0.00309 (164/53010). AF 95% confidence interval is 0.00271. There are 1 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 59 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.618C>T	p.Ser206=	synonymous_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.582C>T	p.Ser194=	synonymous_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.618C>T	p.Ser206=	synonymous_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.582C>T	p.Ser194=	synonymous_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

218

AN:

111669

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

AN XY:

33861

show subpopulations

Gnomad AFR

AF:

0.000686

Gnomad AMI

AF:

0.00733

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.00152

Gnomad EAS

AF:

0.000564

Gnomad SAS

AF:

0.00262

Gnomad FIN

AF:

0.000494

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00230

AC:

421

AN:

183308

Hom.:

AF XY:

0.00233

AC XY:

158

AN XY:

67812

show subpopulations

Gnomad AFR exome

AF:

0.000761

Gnomad AMR exome

AF:

0.00317

Gnomad ASJ exome

AF:

0.000534

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.00225

Gnomad FIN exome

AF:

0.000312

Gnomad NFE exome

AF:

0.00317

Gnomad OTH exome

AF:

0.00243

GnomAD4 exome

AF:

0.00317

AC:

3484

AN:

1098212

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

1117

AN XY:

363574

show subpopulations

Gnomad4 AFR exome

AF:

0.000682

Gnomad4 AMR exome

AF:

0.00304

Gnomad4 ASJ exome

AF:

0.000619

Gnomad4 EAS exome

AF:

0.0000993

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.000518

Gnomad4 NFE exome

AF:

0.00367

Gnomad4 OTH exome

AF:

0.00271

GnomAD4 genome

AF:

0.00195

AC:

218

AN:

111719

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

AN XY:

33923

show subpopulations

Gnomad4 AFR

AF:

0.000684

Gnomad4 AMR

AF:

0.00112

Gnomad4 ASJ

AF:

0.00152

Gnomad4 EAS

AF:

0.000565

Gnomad4 SAS

AF:

0.00263

Gnomad4 FIN

AF:

0.000494

Gnomad4 NFE

AF:

0.00309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00229

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00342

AC:

ExAC

AF:

0.00222

AC:

270

EpiCase

AF:

0.00305

EpiControl

AF:

0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2012	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, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2013	- -

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Rett syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 22, 2024

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

History of neurodevelopmental disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2016

This alteration is classified as benign based on a combination of the following: 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. -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.88

DANN

Benign

0.52

DEOGEN2

Benign

0.075

T;T

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.0081

T;T

MetaSVM

Uncertain

0.49

MutationTaster

Benign

1.0

D;D;N

REVEL

Uncertain

0.47

Sift4G

Uncertain

0.052

T;T

Vest4

0.24

MVP

0.98

ClinPred

0.0073

GERP RS

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over