rs185957513

Positions:

chrX-154030455-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110792.2(MECP2):c.1409G>A(p.Arg470His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,209,420 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 88 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 0.00016 ( 0 hom., 8 hem., cov: 22)

Exomes 𝑓: 0.00019 ( 0 hom. 80 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.70

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056291252).

BP6

Variant X-154030455-C-T is Benign according to our data. Variant chrX-154030455-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030455-C-T is described in Lovd as [Likely_benign]. Variant chrX-154030455-C-T is described in Lovd as [Pathogenic]. Variant chrX-154030455-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000194 (213/1098179) while in subpopulation EAS AF= 0.000894 (27/30206). AF 95% confidence interval is 0.00063. There are 0 homozygotes in gnomad4_exome. There are 80 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1409G>A	p.Arg470His	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.1373G>A	p.Arg458His	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.1409G>A	p.Arg470His	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1373G>A	p.Arg458His	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1
MECP2	ENST00000628176.2 linkuse as main transcript	c.*745G>A		3_prime_UTR_variant	5/5	3		ENSP00000486978

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

111191

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

AN XY:

33373

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000566

Gnomad SAS

AF:

0.000779

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000229

AC:

AN:

183515

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

67943

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00173

Gnomad SAS exome

AF:

0.000419

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000732

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

213

AN:

1098179

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

AN XY:

363533

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000284

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.000894

Gnomad4 SAS exome

AF:

0.000222

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.000162

AC:

AN:

111241

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

33433

show subpopulations

Gnomad4 AFR

AF:

0.000131

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000568

Gnomad4 SAS

AF:

0.000781

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000189

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000759

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 28, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	curation	RettBASE	Nov 05, 2009	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	This variant is associated with the following publications: (PMID: 18810657, 28394482) -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 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 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 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). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2, PMID 18810657, PMID: 18810657). Variant found in a case with an alternate molecular basis for disease (BP5_Supporting, PMID: 18810657). -

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

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

MECP2 NM_004992.3 exon 4 p.Arg458His (c.1373G>A): This variant has been reported in the literature in 1 male individual with features of Rett syndrome, but did not meet diagnostic criteria (reported as p.Arg470His, Zhang 2017 PMID:28394482). This variant is present in 0.01% (10/52947) of European alleles, including 5 hemizygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/X-154030455-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign (Variation ID:95193). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

MECP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2021

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

0.24

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.056

T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.93

N;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;D

Vest4

0.19

MVP

0.98

ClinPred

0.032

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.15

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