rs193922676

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1BP4_ModerateBP6_Very_StrongBS2

The NM_001110792.2(MECP2):c.1187C>T(p.Pro396Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,199,823 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 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 Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P396S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 21)

Exomes 𝑓: 0.000060 ( 0 hom. 23 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:3

Conservation

PhyloP100: 0.209

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 -12 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 11 uncertain in NM_001110792.2

BP4

Computational evidence support a benign effect (MetaRNN=0.1853491).

BP6

Variant X-154030677-G-A is Benign according to our data. Variant chrX-154030677-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36490.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030677-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1187C>T	p.Pro396Leu	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.1151C>T	p.Pro384Leu	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.1187C>T	p.Pro396Leu	missense_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1151C>T	p.Pro384Leu	missense_variant	4/4	1	NM_004992.4	P1	P51608-1
MECP2	ENST00000407218.5 linkuse as main transcript	c.*523C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2 linkuse as main transcript	c.*523C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000183

AC:

AN:

109181

Hom.:

Cov.:

AF XY:

0.0000637

AC XY:

AN XY:

31415

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000194

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:

0.0000115

AC:

AN:

173513

Hom.:

AF XY:

0.00

AC XY:

AN XY:

62963

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000736

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000596

AC:

AN:

1090642

Hom.:

Cov.:

AF XY:

0.0000642

AC XY:

AN XY:

358098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

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:

0.0000703

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

AF:

0.0000183

AC:

AN:

109181

Hom.:

Cov.:

AF XY:

0.0000637

AC XY:

AN XY:

31415

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000194

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:

0.0000756

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Oct 18, 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 likely 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 has been reported in at least 2 individuals with no features of Rett Syndrome by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (BS2). It has been observed in at least 1 individual with phenotypes consistent with MECP2-related disease (PS4_Supporting not met, PMID: 22277191). -
Likely benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 27, 2023	The p.Pro384Leu variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with a neurological condition (PMID 22277191) (PM6). The p.Pro384Leu variant has been observed in 1 additional individual with intellectual disability (PMID 22277191) (not sufficient to meet PS4_supporting criteria). The p.Pro384Leu variant is observed in at least 8 unaffected individuals, most of whom are male (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro384Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The p.Pro384Leu variant in MECP2 is present in 2 female individual(s) in gnomAD (0.0012%) (not sufficient to meet BS1 criteria). In summary, this variant meets the criteria to be classified as Likely Benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: PM6, BS2, BP5 (ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2; date of approval 12/13/2021). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 01, 2016

Variant Summary: The c.1151C>T (p.Pro384Leu) variant involves the alteration of a non-conserved nucleotide resulting in the substitution of a conserved Proline 384 residue by Leucine in the C-Terminal domain of MECP2. Although this amino acid change is considered to be a non-conserved substitution by BLOSUM50 and BLOSUM62, 3/5 in silico tools predict a neutral outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.001% (1/80,748 chromosomes). It has been reported in the literature in 2 patients with nonspecific mental retardation without strong evidence for causality (Zvereff et al, 2012). It was reportedly observed as an inherited variant (unaffected carrier mother) in one case and as a de-novo event in the other. In the absence of an unequivocal confirmation of maternity and paternity, this contradictory evidence cannot be weighted into its classification. The variant has been reported by the RettBase mutation database as a variant of unknown significance citing the report by Zvereff et al, 2012. Therefore, taken together, this variant has been re-classified as a VUS until additional evidence becomes available. -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 384 of the MECP2 protein (p.Pro384Leu). This variant is present in population databases (rs193922676, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 22277191; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 36490). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MECP2 protein function with a negative 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. -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Sep 27, 2012

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2020

This variant is associated with the following publications: (PMID: 22277191) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.23

Cadd

Benign

Dann

Benign

0.41

DEOGEN2

Benign

0.24

T;.

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.37

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.25

T;T

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.34

B;P

Vest4

0.22

MVP

0.91

ClinPred

0.10

GERP RS

2.2

Varity_R

0.051

gMVP

0.40

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