rs61750239

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got -2 ACMG points: 2P and 4B. PP3PP4BS2

This summary comes from the ClinGen Evidence Repository: The p.Arg268Trp variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (PMID 12750821, internal database - Invitae) (BS2). The p.Arg268Trp variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 18842453) (PP4). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg268Trp variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.0009792% (no criteria met). In summary, the p.Arg268Trp variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA233007/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. 3 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:6B:2O:1

Conservation

PhyloP100: 5.13

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 Uncertain_significance. Variant got -2 ACMG points.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.838C>T	p.Arg280Trp	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.802C>T	p.Arg268Trp	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.838C>T	p.Arg280Trp	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.802C>T	p.Arg268Trp	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000355

AC:

AN:

112533

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34697

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000930

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000548

AC:

AN:

182455

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67367

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1098176

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363548

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000285

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000355

AC:

AN:

112533

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34697

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000930

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000526

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Benign:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2019	Reported as pathogenic [in ClinVar/in a well-curated database/through personal communication] but additional evidence is not available [ref]; Reported as pathogenic [in ClinVar/in a well-curated database/through personal communication] but additional evidence is not available [ref]; This variant is associated with the following publications: (PMID: 11469283, 18842453, 12750821) -
not provided, no classification provided	literature only	RettBASE	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 268 of the MECP2 protein (p.Arg268Trp). This variant is present in population databases (rs61750239, gnomAD 0.002%). This missense change has been observed in individual(s) with X-linked intellectual disability and/or Rett syndrome (PMID: 11469283, 12750821, 18842453). ClinVar contains an entry for this variant (Variation ID: 143700). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Rett syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Oct 28, 2021

The p.Arg268Trp variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (PMID 12750821, internal database - Invitae) (BS2). The p.Arg268Trp variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 18842453) (PP4). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg268Trp variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.0009792% (no criteria met). In summary, the p.Arg268Trp variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PP3, PP4). -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

Unlikely to be causative of Rett syndrome (XLD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

MECP2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

The MECP2 c.802C>T variant is predicted to result in the amino acid substitution p.Arg268Trp. This variant was reported in an individual with Rett syndrome; however, the individual also harbored a nonsense variant two amino acids downstream, with both changes reported as de novo (p.[Arg268Trp(;) Arg270*]; Erlandson et al 2001. PubMed ID: 11469283; http://mecp2.chw.edu.au/). Two additional papers document this variant in at least three individuals with Rett Syndrome or X-linked intellectual disability 13, yet these patients are not characterized (Renieri et al. 2003. PubMed ID: 12750821; Buoni et al. 2008. PubMed ID: 18842453). This variant is reported in 0.0022% of alleles in individuals of European (non-Finnish) descent in gnomAD V2 and has been reported in 4 hemizygotes in updated gnomAD V4 data (https://gnomad.broadinstitute.org/variant/X-154031026-G-A?dataset=gnomad_r4). To our knowledge, no functional studies have been done to support this variant's pathogenicity. Other labs report this missense change as either a variant of uncertain significance or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/143700/). X-inactivation skewing may alter disease severity in females with pathogenic MECP2 alterations. At this time, the clinical significance of this variant is uncertain due to insufficient functional and genetic evidence. -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.2

D;D;.

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.034

D;T;D

Polyphen

1.0

D;D;.

Vest4

0.66

MVP

1.0

ClinPred

0.92

GERP RS

4.7

Varity_R

0.62

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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