rs141382970

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.748C>T p.Arg250Cys variant in MECP2 (NM_004992.3) is present in 1 XY and 4 XX individuals in gnomAD (0.0034% in the European non-Finnish population) (not sufficient to meet BS1 criteria). The p.Arg250Cys variant is observed in at least 2 unaffected individuals (GeneDx internal data) (BS2). The p.Arg250Cys variant has been observed in at least 1 individual with RTT-like disease (PMID 30405208); however PS4 cannot be applied at any strength due to the gnomAD frequency. Computational prediction analysis tools are inconclusive for this variant (criteria not met). Alternative missense variants (p.Arg250Gly and p.Arg250His) have previously been identified within this codon, however they are not considered to be pathogenic variants (PMID 30405208; RettBASE: RettSyndrome.org Variation Database mecp2.chw.edu.au). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the c.748C>T p.Arg250Cys variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA205183/MONDO:0010726/036

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000047 ( 0 hom. 21 hem. )

Consequence

MECP2
ENST00000453960.7 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:3

Conservation

PhyloP100: 4.93

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 Likely_benign. Variant got -4 ACMG points.

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.784C>T	p.Arg262Cys	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.748C>T	p.Arg250Cys	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.784C>T	p.Arg262Cys	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.748C>T	p.Arg250Cys	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00000887

AC:

AN:

112767

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34911

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

182990

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67600

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.0000368

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000474

AC:

AN:

1098086

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

363450

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000523

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.00000887

AC:

AN:

112767

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34911

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2018	The MECP2 c.748C>T; p.Arg250Cys variant (rs141382970), to our knowledge, has not been reported in the medical literature but is reported as benign by one laboratory in ClinVar (Variation ID: 211466). This variant is observed in the general population at an overall frequency of 0.002% (5/178458 alleles, including 1 hemizygote) in the Genome Aggregation Database. The arginine at codon 250 is highly conserved, and computational algorithms (PolyPhen2, SIFT) predict this variant to be deleterious. However, additional variants at this codon (p.Arg250Arg, p.Arg250His) are considered as polymorphisms that do not cause disease (see link for Rett database). Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Link to Rett database: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 250 of the MECP2 protein (p.Arg250Cys). This variant is present in population databases (rs141382970, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 30405208). ClinVar contains an entry for this variant (Variation ID: 211466). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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. -

MECP2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

The MECP2 c.748C>T variant is predicted to result in the amino acid substitution p.Arg250Cys. This variant has been reported in a patient with a MECP2 related disorder; however, no additional studies confirmed its pathogenicity (Zhang et al. 2019. PubMed ID: 30405208). This variant is reported in 0.0063% of alleles in individuals of European (Finnish) descent in gnomAD. It has been detected in the heterozygous and hemizygous states in both the gnomAD database and the PreventionGenetics internal database at a frequency that is higher than expected for a disease-causing MECP2 variant, and is observed in individuals not expected to have a MECP2-related disease. Alternate missense changes at the same amino acid position have been reported in gnomAD, and as non-disease-causing variants in the Rett database (http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic; https://gnomad.broadinstitute.org/region/X-153296511-153296551). This variant has conflicting classifications in ClinVar of Uncertain, Likely Benign, and Benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/211466/). Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Rett syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Dec 06, 2023

The c.748C>T p.Arg250Cys variant in MECP2 (NM_004992.3) is present in 1 XY and 4 XX individuals in gnomAD (0.0034% in the European non-Finnish population) (not sufficient to meet BS1 criteria). The p.Arg250Cys variant is observed in at least 2 unaffected individuals (GeneDx internal data) (BS2). The p.Arg250Cys variant has been observed in at least 1 individual with RTT-like disease (PMID 30405208); however PS4 cannot be applied at any strength due to the gnomAD frequency. Computational prediction analysis tools are inconclusive for this variant (criteria not met). Alternative missense variants (p.Arg250Gly and p.Arg250His) have previously been identified within this codon, however they are not considered to be pathogenic variants (PMID 30405208; RettBASE: RettSyndrome.org Variation Database mecp2.chw.edu.au). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the c.748C>T p.Arg250Cys variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;.;T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.3

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.5

D;D;.;.

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Uncertain

0.011

D;D;.;D

Polyphen

1.0

D;D;.;.

Vest4

0.66

MVP

1.0

ClinPred

0.61

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.69

gMVP

0.96

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