X-154030501-C-T

Position:

chrX-154030501-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala443Thr variant in MECP2 (NM_004992.3) is 0.015% in Latino population and 0.014% in East Asian 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). The p.Ala443Thr variant is observed in at least 2 unaffected individuals (RettBASE, PMID 22277191, GeneDx internal database, Invitae internal database) (BS2). In summary, the p.Ala443Thr variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199489/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000095 ( 0 hom. 32 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:7

Conservation

PhyloP100: 1.40

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.

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.1363G>A	p.Ala455Thr	missense_variant	3/3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 linkuse as main transcript	c.1327G>A	p.Ala443Thr	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.1363G>A	p.Ala455Thr	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1327G>A	p.Ala443Thr	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6	P51608-1
MECP2	ENST00000628176 linkuse as main transcript	c.*699G>A		3_prime_UTR_variant	5/5	3		ENSP00000486978.1	A0A0D9SFX7

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

111516

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33698

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.000766

Gnomad FIN

AF:

0.000165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000873

AC:

AN:

183347

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

67807

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.0000627

Gnomad NFE exome

AF:

0.0000855

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000947

AC:

104

AN:

1098183

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

363549

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.000199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.0000741

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.000117

AC:

AN:

111568

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33760

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.000189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000283

Gnomad4 SAS

AF:

0.000768

Gnomad4 FIN

AF:

0.000165

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000151

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:7

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	Jul 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2020	This variant is associated with the following publications: (PMID: 22277191) -

Rett syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 10, 2024	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 3.0, 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). -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Feb 18, 2022	The allele frequency of the p.Ala443Thr variant in MECP2 (NM_004992.3) is 0.015% in Latino population and 0.014% in East Asian 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). The p.Ala443Thr variant is observed in at least 2 unaffected individuals (RettBASE, PMID 22277191, GeneDx internal database, Invitae internal database) (BS2). In summary, the p.Ala443Thr variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 01, 2016

Variant Summary: The c.1327G>A variant involves the alteration of a non-conserved nucleotide resulting in substitution of a non-conserved Alanine 443 residue with Threonine in the C-Terminal domain of the MECP2 gene. 4/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.006% (5/87652 chromosomes tested), predominantly in individuals of European descent (0.006% or 3/47913 chromosomes, including 1 presumably healthy adult hemizygous male). The variant was reported in the literature in 2 patients: as a maternally inherited variant in one male patient with nonspecific mental retardation without strong evidence for causality (Zvereff et al, 2012) and in a female patient reportedly diagnosed based on clinical evaluation performed according to the Rett Assessment Rating Scale (RARS) (Isaias et al, 2014). No information about segregation as well as XCI data was available for the patient described by Isias et al. The variant has been reported by the RettBase mutation database as a variant of unknown significance citing the report by Zvereff et al. Based on its prevalence in healthy controls, including one male individual, this variant is unlikely to be associated with the pathophysiology of Rett syndrome. However, its involvement in other types non-syndromic X-linked mental retardation cannot entirely be excluded. Therefore, this variant was classified as a VUS-possibly benign, until more information becomes available. -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Sep 27, 2012

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

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. -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2022

This variant is classified as likely 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

0.072

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.39

T;.

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.078

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.34

N;.

PrimateAI

Benign

0.38

PROVEAN

Benign

0.080

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.85

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.0020

B;B

Vest4

0.14

MVP

0.89

ClinPred

0.014

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.035

gMVP

0.51

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