rs61748424

Positions:

Variant summary

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

The NM_001110792.2(MECP2):c.786C>T(p.Arg262=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,210,984 control chromosomes in the GnomAD database, including 1 homozygotes. There are 230 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 0.00032 ( 0 hom., 14 hem., cov: 23)

Exomes 𝑓: 0.00061 ( 1 hom. 216 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.108

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 (BayesDel_noAF=-0.55).

BP6

Variant X-154031078-G-A is Benign according to our data. Variant chrX-154031078-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031078-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.108 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000607 (666/1098102) while in subpopulation EAS AF= 0.000762 (23/30201). AF 95% confidence interval is 0.000653. There are 1 homozygotes in gnomad4_exome. There are 216 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.786C>T	p.Arg262=	synonymous_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.750C>T	p.Arg250=	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.786C>T	p.Arg262=	synonymous_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.750C>T	p.Arg250=	synonymous_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000319

AC:

AN:

112829

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

AN XY:

34967

show subpopulations

Gnomad AFR

AF:

0.0000644

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000185

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000362

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000582

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000273

AC:

AN:

182959

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

67589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000454

Gnomad OTH exome

AF:

0.000665

GnomAD4 exome

AF:

0.000607

AC:

666

AN:

1098102

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

216

AN XY:

363466

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000762

Gnomad4 SAS exome

AF:

0.000332

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000700

Gnomad4 OTH exome

AF:

0.000607

GnomAD4 genome

AF:

0.000319

AC:

AN:

112882

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

AN XY:

35030

show subpopulations

Gnomad4 AFR

AF:

0.0000643

Gnomad4 AMR

AF:

0.000185

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000363

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000582

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000727

Hom.:

Bravo

AF:

0.000359

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MECP2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Rett syndrome

Benign:1

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 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). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2016

This alteration is classified as likely 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. -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 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_noAF

Benign

-0.55

CADD

Benign

6.8

DANN

Benign

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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