rs61749714

Positions:

Variant summary

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

The NM_001110792.2(MECP2):c.626C>T(p.Thr209Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,209,741 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 226 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00055 ( 0 hom. 217 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.46

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 (BayesDel_addAF=-0.65758).

BP6

Variant X-154031238-G-A is Benign according to our data. Variant chrX-154031238-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031238-G-A is described in Lovd as [Likely_benign]. Variant chrX-154031238-G-A is described in Lovd as [Pathogenic]. Variant chrX-154031238-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000551 (605/1098256) while in subpopulation SAS AF= 0.00181 (98/54149). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4_exome. There are 217 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.626C>T	p.Thr209Met	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.590C>T	p.Thr197Met	missense_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.626C>T	p.Thr209Met	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.590C>T	p.Thr197Met	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000431

AC:

AN:

111431

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

33647

show subpopulations

Gnomad AFR

AF:

0.000295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000844

Gnomad SAS

AF:

0.00114

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000566

Gnomad OTH

AF:

0.000665

GnomAD3 exomes

AF:

0.000643

AC:

118

AN:

183393

Hom.:

AF XY:

0.000634

AC XY:

AN XY:

67859

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000505

Gnomad SAS exome

AF:

0.00220

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000464

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000551

AC:

605

AN:

1098256

Hom.:

Cov.:

AF XY:

0.000597

AC XY:

217

AN XY:

363612

show subpopulations

Gnomad4 AFR exome

AF:

0.000227

Gnomad4 AMR exome

AF:

0.000966

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000596

Gnomad4 SAS exome

AF:

0.00181

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000500

Gnomad4 OTH exome

AF:

0.000542

GnomAD4 genome

AF:

0.000431

AC:

AN:

111485

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

33711

show subpopulations

Gnomad4 AFR

AF:

0.000294

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000847

Gnomad4 SAS

AF:

0.00114

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000566

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.000473

Hom.:

Bravo

AF:

0.000563

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000948

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, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.1% (15/10125) South Asian chromosomes. Duplication of gene associated with intellectual disability, hypotonia, seizures, spasticity. SNVs associated with Rett syndrome. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2013	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	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2014	- -

Rett syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 2023	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 2.0, 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 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2015	The observed allele frequency of this variant in the large and diverse ExAC cohort is 48/87676 (1/1827) with 20 hemizygotes, suggesting that it is a benign polymorphism. The variant is classified as a polymorphism/not disease-causing in the literature, and has been shown to not co-segregate with disease in at least 2 families. Variant was observed in cis with pathogenic MECP2 variants (c.473C>T/p.T158M, c.916C>T/p.R306C) in multiple RTT patients. -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2017

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 05, 2014

- -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2021

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

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.50

MutationTaster

Benign

1.0

D;N;N

Vest4

0.65

ClinPred

0.0069

GERP RS

3.3

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