rs63485860

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2BS1BP5_Strong

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Gly206Ala variant in MECP2 (NM_004992.3) is 0.008% in the European (non-Finnish) 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). The p.Gly206Ala variant in MECP2 is observed in at least 2 unaffected individuals (PMID 17427193, internal database - GeneDx) (BS2). The p.Gly206Ala variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). In summary, the p.Gly206Ala variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170346/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000087 ( 0 hom. 26 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 3.65

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP5

BS1

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.653G>C	p.Gly218Ala	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.617G>C	p.Gly206Ala	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.653G>C	p.Gly218Ala	missense_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.617G>C	p.Gly206Ala	missense_variant	4/4	1	NM_004992.4	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000811

AC:

AN:

110910

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

33090

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:

0.000171

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183510

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67940

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:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000874

AC:

AN:

1098263

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

363621

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000811

AC:

AN:

110910

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

33090

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:

0.000171

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000642

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 14, 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 allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). (PMID 1742719, ClinVar Variation ID: 143638) -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 11, 2022	The allele frequency of the p.Gly206Ala variant in MECP2 (NM_004992.3) is 0.008% in the European (non-Finnish) 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). The p.Gly206Ala variant in MECP2 is observed in at least 2 unaffected individuals (PMID 17427193, internal database - GeneDx) (BS2). The p.Gly206Ala variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx; internal database - Invitae) (BP5_strong). In summary, the p.Gly206Ala variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5_strong). -

Autism, susceptibility to, X-linked 3

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Nov 01, 2007

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2018

This variant is associated with the following publications: (PMID: 17427193, 26350204) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.59

CADD

Benign

DANN

Benign

0.51

DEOGEN2

Uncertain

0.57

D;.;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Uncertain

0.58

D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.3

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.5

N;N;.;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

D;D;.;.

Sift4G

Benign

0.34

T;T;.;T

Polyphen

1.0

D;D;.;.

Vest4

0.46

MVP

1.0

ClinPred

0.33

GERP RS

5.5

Varity_R

0.51

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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