rs61748423

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.933C>T(p.Thr311=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,210,623 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,171 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., 58 hem., cov: 23)

Exomes 𝑓: 0.0031 ( 4 hom. 1113 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.609

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=0.008170664).

BP6

Variant X-154030931-G-A is Benign according to our data. Variant chrX-154030931-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030931-G-A is described in Lovd as [Likely_benign]. Variant chrX-154030931-G-A is described in Lovd as [Benign]. Variant chrX-154030931-G-A is described in Lovd as [Pathogenic].

BP7

Synonymous conserved (PhyloP=-0.609 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00203 (228/112391) while in subpopulation NFE AF= 0.00292 (155/53129). AF 95% confidence interval is 0.00254. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 58 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.933C>T	p.Thr311=	synonymous_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.897C>T	p.Thr299=	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.933C>T	p.Thr311=	synonymous_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.897C>T	p.Thr299=	synonymous_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

228

AN:

112339

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

AN XY:

34497

show subpopulations

Gnomad AFR

AF:

0.000485

Gnomad AMI

AF:

0.0630

Gnomad AMR

AF:

0.000747

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000560

Gnomad SAS

AF:

0.000727

Gnomad FIN

AF:

0.000163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00292

Gnomad OTH

AF:

0.00133

GnomAD3 exomes

AF:

0.00180

AC:

330

AN:

183486

Hom.:

AF XY:

0.00166

AC XY:

113

AN XY:

67930

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.000911

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.000505

Gnomad SAS exome

AF:

0.000681

Gnomad FIN exome

AF:

0.000437

Gnomad NFE exome

AF:

0.00328

Gnomad OTH exome

AF:

0.000883

GnomAD4 exome

AF:

0.00307

AC:

3376

AN:

1098232

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

1113

AN XY:

363590

show subpopulations

Gnomad4 AFR exome

AF:

0.000985

Gnomad4 AMR exome

AF:

0.000937

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.000563

Gnomad4 SAS exome

AF:

0.000739

Gnomad4 FIN exome

AF:

0.000469

Gnomad4 NFE exome

AF:

0.00370

Gnomad4 OTH exome

AF:

0.00267

GnomAD4 genome

AF:

0.00203

AC:

228

AN:

112391

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

AN XY:

34559

show subpopulations

Gnomad4 AFR

AF:

0.000484

Gnomad4 AMR

AF:

0.000746

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000562

Gnomad4 SAS

AF:

0.000729

Gnomad4 FIN

AF:

0.000163

Gnomad4 NFE

AF:

0.00292

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00254

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00381

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00357

AC:

ExAC

AF:

0.00178

AC:

216

EpiCase

AF:

0.00453

EpiControl

AF:

0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 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	Eurofins Ntd Llc (ga)	Dec 27, 2012	- -
Benign, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -
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	-	- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 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). -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 17, 2021

- -

History of neurodevelopmental disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2016

Other strong data supporting benign classification;Synonymous alterations with insufficient evidence to classify as benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

2.9

DANN

Benign

0.75

DEOGEN2

Benign

0.086

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0082

MutationTaster

Benign

1.0

D;D

Sift4G

Uncertain

0.053

Vest4

0.39

MVP

0.77

GERP RS

2.2

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