rs267608492

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5

The NM_001110792.2(MECP2):c.554C>G(p.Pro185Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,210,509 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P185A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000091 ( 0 hom. 6 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 9.39

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 Uncertain_significance. Variant got 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154031311-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 804125.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.554C>G	p.Pro185Arg	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.518C>G	p.Pro173Arg	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.554C>G	p.Pro185Arg	missense_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.518C>G	p.Pro173Arg	missense_variant	4/4	1	NM_004992.4	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34406

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183154

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67646

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1098243

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363597

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000712

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34406

show subpopulations

Gnomad4 AFR

AF:

0.0000324

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2016	- -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Feb 15, 2011	- -

Rett syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 09, 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 likely benign. At least the following criteria are met: The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_Supporting). ( RettBASE, PMID 23696494). The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 07, 2015	- -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual with Rett syndrome as inherited from an unaffected mother with random X-chromosome inactivation, however, that individual also carried another variant that was de novo and in trans(on the opposite chromosome) with this variant (PMID: 23696494). ClinVar contains an entry for this variant (Variation ID: 143609). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 173 of the MECP2 protein (p.Pro173Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.34

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.7

N;N;.;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.029

D;D;.;.

Sift4G

Uncertain

0.0040

D;D;.;D

Polyphen

0.99

D;D;.;.

Vest4

0.34

MutPred

0.29

Loss of glycosylation at P173 (P = 0.0016);.;Loss of glycosylation at P173 (P = 0.0016);.;

MVP

0.93

ClinPred

0.71

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.88

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