rs61753971

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001110792.2(MECP2):c.1318G>A(p.Gly440Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,208,496 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. G440G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000061 ( 0 hom. 23 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1B:7

Conservation

PhyloP100: 2.49

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23069146).

BP6

Variant X-154030546-C-T is Benign according to our data. Variant chrX-154030546-C-T is described in ClinVar as [Benign]. Clinvar id is 11831.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030546-C-T is described in Lovd as [Likely_benign]. Variant chrX-154030546-C-T is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1318G>A	p.Gly440Ser	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.1282G>A	p.Gly428Ser	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.1318G>A	p.Gly440Ser	missense_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1282G>A	p.Gly428Ser	missense_variant	4/4	1	NM_004992.4	P1	P51608-1
MECP2	ENST00000628176.2 linkuse as main transcript	c.*654G>A		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000993

AC:

AN:

110805

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

33021

show subpopulations

Gnomad AFR

AF:

0.0000658

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000957

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

182729

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

67265

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000314

Gnomad FIN exome

AF:

0.0000642

Gnomad NFE exome

AF:

0.000122

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000610

AC:

AN:

1097691

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363127

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.0000998

Gnomad4 NFE exome

AF:

0.0000534

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000993

AC:

AN:

110805

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

33021

show subpopulations

Gnomad4 AFR

AF:

0.0000658

Gnomad4 AMR

AF:

0.0000957

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000167

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -

Rett syndrome

Benign:2

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: 11238684). -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	May 10, 2022	The allele frequency of the p.Gly428Ser (NM_004992) variant in MECP2 is 0.014% in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly428Ser variant is observed in at least 2 unaffected individuals (PMID: 11238684, PMID: 12161600) (BS2). In summary the p.Gly428Ser variant in MECP2 is classified as Benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2). -

not specified

Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Oct 04, 2002

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2019

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

This variant is associated with the following publications: (PMID: 28454995, 11238684, 12161600, 11896461, 30560934) -

MECP2-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 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

0.090

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.16

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.26

T;.

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

-0.093

MutationAssessor

Benign

0.46

N;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.020

N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.44

T;T

Polyphen

0.96

D;D

Vest4

0.13

MVP

1.0

ClinPred

0.057

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.20

gMVP

0.14

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