rs61748381

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110792.2(MECP2):c.638C>T(p.Ala213Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,209,384 control chromosomes in the GnomAD database, including 6 homozygotes. There are 380 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A213A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., 41 hem., cov: 23)

Exomes 𝑓: 0.0010 ( 6 hom. 339 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1B:17

Conservation

PhyloP100: 2.69

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053327978).

BP6

Variant X-154031226-G-A is Benign according to our data. Variant chrX-154031226-G-A is described in ClinVar as [Benign]. Clinvar id is 138188.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154031226-G-A is described in Lovd as [Likely_benign]. Variant chrX-154031226-G-A is described in Lovd as [Benign]. Variant chrX-154031226-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00163 (181/111134) while in subpopulation EAS AF= 0.0119 (42/3530). AF 95% confidence interval is 0.00905. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 41 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.638C>T	p.Ala213Val	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.602C>T	p.Ala201Val	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.638C>T	p.Ala213Val	missense_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.602C>T	p.Ala201Val	missense_variant	4/4	1	NM_004992.4	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

181

AN:

111078

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

33306

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00274

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0119

Gnomad SAS

AF:

0.00153

Gnomad FIN

AF:

0.000333

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00135

GnomAD3 exomes

AF:

0.00143

AC:

262

AN:

183434

Hom.:

AF XY:

0.00130

AC XY:

AN XY:

67882

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.000547

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0106

Gnomad SAS exome

AF:

0.000734

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.000806

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.00100

AC:

1103

AN:

1098250

Hom.:

Cov.:

AF XY:

0.000932

AC XY:

339

AN XY:

363604

show subpopulations

Gnomad4 AFR exome

AF:

0.00193

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0129

Gnomad4 SAS exome

AF:

0.000979

Gnomad4 FIN exome

AF:

0.000247

Gnomad4 NFE exome

AF:

0.000617

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00163

AC:

181

AN:

111134

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

33372

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0119

Gnomad4 SAS

AF:

0.00154

Gnomad4 FIN

AF:

0.000333

Gnomad4 NFE

AF:

0.00121

Gnomad4 OTH

AF:

0.00133

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.00204

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.00154

AC:

187

EpiCase

AF:

0.00109

EpiControl

AF:

0.000889

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2016	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	Genetic Services Laboratory, University of Chicago	Jun 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2014	- -

not provided

Benign:5

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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 10, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Rett syndrome

Pathogenic:1Benign:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Aug 17, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	May 10, 2022	The allele frequency of the p.Ala201Val (NM_004992) variant in MECP2 is 1.045% in East Asian sub population in gnomAD, which is high enough to be classified as Benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Ala201Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1). -
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). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

History of neurodevelopmental disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2016

Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Subpopulation frequency in support of benign classification -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.;T;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0053

T;T;T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

-0.35

N;.;.;.

MutationTaster

Benign

0.55

D;D;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.60

N;N;.;.

REVEL

Uncertain

0.44

Sift

Benign

0.11

T;T;.;.

Sift4G

Benign

0.30

T;T;.;T

Polyphen

0.0020

B;B;.;.

Vest4

0.051

MVP

1.0

ClinPred

0.0038

GERP RS

4.6

Varity_R

0.086

gMVP

0.35

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