rs61748422

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001110792.2(MECP2):c.731G>C(p.Gly244Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000558 in 1,206,746 control chromosomes in the GnomAD database, including 8 homozygotes. There are 214 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00059 ( 8 hom. 206 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.58

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=0.00890398).

BP6

Variant X-154031133-C-G is Benign according to our data. Variant chrX-154031133-C-G is described in ClinVar as [Benign]. Clinvar id is 143661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031133-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000253 (28/110714) while in subpopulation EAS AF= 0.00718 (25/3482). AF 95% confidence interval is 0.00499. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.731G>C	p.Gly244Ala	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.695G>C	p.Gly232Ala	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.731G>C	p.Gly244Ala	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.695G>C	p.Gly232Ala	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000253

AC:

AN:

110662

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

32912

show subpopulations

Gnomad AFR

AF:

0.0000330

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00716

Gnomad SAS

AF:

0.000392

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000185

AC:

AN:

183387

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

67859

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00188

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000588

AC:

645

AN:

1096032

Hom.:

Cov.:

AF XY:

0.000570

AC XY:

206

AN XY:

361712

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0205

Gnomad4 SAS exome

AF:

0.000259

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000261

GnomAD4 genome

AF:

0.000253

AC:

AN:

110714

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

32974

show subpopulations

Gnomad4 AFR

AF:

0.0000329

Gnomad4 AMR

AF:

0.0000948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00718

Gnomad4 SAS

AF:

0.000393

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000198

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 10, 2010

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

May 03, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome

Benign:1

Aug 14, 2023

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30564305) -

MECP2-related disorder

Benign:1

May 25, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

0.075

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.27

T;.;T;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.0089

T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.55

N;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.55

N;N;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.19

T;T;.;.

Sift4G

Benign

0.58

T;T;.;T

Polyphen

0.023

B;B;.;.

Vest4

0.10

MVP

0.99

ClinPred

0.022

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.43

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