rs3027928

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001110792.2(MECP2):c.1269C>T(p.Ser423=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,204,764 control chromosomes in the GnomAD database, including 1,069 homozygotes. There are 3,208 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 164 hom., 595 hem., cov: 22)

Exomes 𝑓: 0.0089 ( 905 hom. 2613 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.187

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=-0.76).

BP6

Variant X-154030595-G-A is Benign according to our data. Variant chrX-154030595-G-A is described in ClinVar as [Benign]. Clinvar id is 95189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030595-G-A is described in Lovd as [Benign]. Variant chrX-154030595-G-A is described in Lovd as [Pathogenic].

BP7

Synonymous conserved (PhyloP=-0.187 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1269C>T	p.Ser423=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.1233C>T	p.Ser411=	synonymous_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.1269C>T	p.Ser423=	synonymous_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1233C>T	p.Ser411=	synonymous_variant	4/4	1	NM_004992.4	P1	P51608-1
MECP2	ENST00000628176.2 linkuse as main transcript	c.*605C>T		3_prime_UTR_variant	5/5	3
MECP2	ENST00000407218.5 linkuse as main transcript			downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0181

AC:

1966

AN:

108878

Hom.:

159

Cov.:

AF XY:

0.0188

AC XY:

588

AN XY:

31200

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00259

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000306

Gnomad OTH

AF:

0.0384

GnomAD3 exomes

AF:

0.0392

AC:

7070

AN:

180207

Hom.:

706

AF XY:

0.0278

AC XY:

1830

AN XY:

65727

show subpopulations

Gnomad AFR exome

AF:

0.00376

Gnomad AMR exome

AF:

0.248

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00144

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000702

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.0453

GnomAD4 exome

AF:

0.00891

AC:

9761

AN:

1095840

Hom.:

905

Cov.:

AF XY:

0.00722

AC XY:

2613

AN XY:

362120

show subpopulations

Gnomad4 AFR exome

AF:

0.00337

Gnomad4 AMR exome

AF:

0.248

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00937

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.0000783

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.0116

GnomAD4 genome

AF:

0.0182

AC:

1983

AN:

108924

Hom.:

164

Cov.:

AF XY:

0.0190

AC XY:

595

AN XY:

31256

show subpopulations

Gnomad4 AFR

AF:

0.00455

Gnomad4 AMR

AF:

0.174

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00260

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000306

Gnomad4 OTH

AF:

0.0379

Alfa

AF:

0.00881

Hom.:

Bravo

AF:

0.0351

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:11

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2017	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2016	Variant Summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico programs via Alamut predicting no significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2425/86448 (1/35 including 248 homozygotes and 583 hemizygotes), which significantly exceeds the predicted maximum expected allele frequency for a pathogenic MECP2 variant of 1/120481. In addition, multiple reputable database/clinical laboratories cite the variant with a classification of "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 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). 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). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

History of neurodevelopmental disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

Cadd

Benign

2.2

Dann

Benign

0.67

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