rs140258520

Positions:

chrX-154030573-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PS4_SupportingBP5BS1BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro419Ser variant in MECP2 (NM_004992.3) is 0.02% in "Other" sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1) and additionally is present in three male individuals in gnomAD. The p.Pro419Ser variant is observed in at least 7 unaffected individuals (Baylor Genetic internal database, GeneDx internal database, PMID 16225173) (BS2). The p.Pro419Ser variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Pro419Ser variant has been observed in at least 2 individuals with neurodevelopmental disorders (PMID 32457807, 16225173) (PS4_supporting), however in these studies MECP2 was the only gene sequenced. In summary the p.Pro419Ser variant in MECP2 is classified as benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5) and the PS4_supporting evidence is not considered inconsistent with the final benign classification. LINK:https://erepo.genome.network/evrepo/ui/classification/CA198850/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000068 ( 0 hom. 24 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:6

Conservation

PhyloP100: 2.72

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 -8 ACMG points.

PS4

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

BP5

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

BS1

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.1291C>T	p.Pro431Ser	missense_variant	3/3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 linkuse as main transcript	c.1255C>T	p.Pro419Ser	missense_variant	4/4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1291C>T	p.Pro431Ser	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1255C>T	p.Pro419Ser	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6	P51608-1
MECP2	ENST00000628176 linkuse as main transcript	c.*627C>T		3_prime_UTR_variant	5/5	3		ENSP00000486978.1	A0A0D9SFX7
MECP2	ENST00000407218.5 linkuse as main transcript	c.*627C>T		downstream_gene_variant		5		ENSP00000384865.2	B5MCB4

Frequencies

GnomAD3 genomes

AF:

0.0000363

AC:

AN:

110124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32402

show subpopulations

Gnomad AFR

AF:

0.0000331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000965

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:

0.0000380

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000550

AC:

AN:

181956

Hom.:

AF XY:

0.0000450

AC XY:

AN XY:

66680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000737

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000684

AC:

AN:

1096824

Hom.:

Cov.:

AF XY:

0.0000662

AC XY:

AN XY:

362574

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000170

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000748

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.0000363

AC:

AN:

110124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32402

show subpopulations

Gnomad4 AFR

AF:

0.0000331

Gnomad4 AMR

AF:

0.0000965

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000380

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Previously reported as a variant of uncertain significance in a female diagnosed with Rett syndrome and her unaffected mother (Gauthier et al., 2005); This variant is associated with the following publications: (PMID: 16225173, 32457807) -

Rett syndrome

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Apr 28, 2022	The allele frequency of the p.Pro419Ser variant in MECP2 (NM_004992.3) is 0.02% in "Other" sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1) and additionally is present in three male individuals in gnomAD. The p.Pro419Ser variant is observed in at least 7 unaffected individuals (Baylor Genetic internal database, GeneDx internal database, PMID 16225173) (BS2). The p.Pro419Ser variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Pro419Ser variant has been observed in at least 2 individuals with neurodevelopmental disorders (PMID 32457807, 16225173) (PS4_supporting), however in these studies MECP2 was the only gene sequenced. In summary the p.Pro419Ser variant in MECP2 is classified as benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5) and the PS4_supporting evidence is not considered inconsistent with the final benign classification. -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Sep 25, 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 variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

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

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2018

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2024

This variant is classified as 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

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

T;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.90

L;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.045

D;T

Polyphen

0.025

B;B

Vest4

0.27

MVP

0.99

ClinPred

0.037

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.10

gMVP

0.32

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