rs782467549

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_001386137.1(MECP2):c.-108C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,210,446 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.0000073 ( 0 hom. 2 hem. )

Consequence

MECP2
NM_001386137.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.11

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 Likely_benign. Variant got -1 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.598C>T	p.Arg200Trp	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.562C>T	p.Arg188Trp	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.598C>T	p.Arg200Trp	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.562C>T	p.Arg188Trp	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112215

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34373

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:

183246

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67750

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000728

AC:

AN:

1098231

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363589

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:

0.0000185

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:

112215

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34373

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

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 11, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MECP2: PP3, BP5 -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 188 of the MECP2 protein (p.Arg188Trp). This variant is present in population databases (rs782467549, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 566728). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.;T;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.6

D;D;.;.

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Uncertain

0.0080

D;D;.;D

Polyphen

1.0

D;D;.;.

Vest4

0.64

MutPred

0.36

Loss of methylation at R188 (P = 0.0029);.;Loss of methylation at R188 (P = 0.0029);.;

MVP

0.98

ClinPred

0.92

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.75

gMVP

0.83

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