rs267608402

Positions:

chrX-154030650-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2BP5

This summary comes from the ClinGen Evidence Repository: The p.Pro393Leu variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Ambry, internal database - Invitae) (BS2). The p.Pro393Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Ambry) (BP5). The highest population minor allele frequency of the p.Pro393Leu variant in MECP2 in gnomAD v4.1 is 0.00002210 in Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Pro393Leu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA232923/MONDO:0010726/036

Frequency

Genomes: 𝑓 0.0000094 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:2O:1

Conservation

PhyloP100: 3.38

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 -5 ACMG points.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1214C>T	p.Pro405Leu	missense_variant	3/3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1178C>T	p.Pro393Leu	missense_variant	4/4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MECP2	ENST00000453960.7 link	c.1214C>T	p.Pro405Leu	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11 link	c.1178C>T	p.Pro393Leu	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6	P51608-1
MECP2	ENST00000407218 link	c.*550C>T		3_prime_UTR_variant	4/4	5		ENSP00000384865.2	B5MCB4
MECP2	ENST00000628176 link	c.*550C>T		3_prime_UTR_variant	5/5	3		ENSP00000486978.1	A0A0D9SFX7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

106288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28742

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000994

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

GnomAD4 exome

AF:

9.16e-7

AC:

AN:

1091695

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359509

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000941

AC:

AN:

106288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28742

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000994

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

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Likely benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 30, 2024	The p.Pro393Leu variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Ambry, internal database - Invitae) (BS2). The p.Pro393Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Ambry) (BP5). The highest population minor allele frequency of the p.Pro393Leu variant in MECP2 in gnomAD v4.1 is 0.00002210 in Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Pro393Leu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). -
Likely benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	May 03, 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 allele frequency of this variant in at least one population in gnomAD v3 is between 0.008% and 0.03% (BS1). -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces proline with leucine at codon 393 of the MECP2 protein (p.Pro393Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 28186668). ClinVar contains an entry for this variant (Variation ID: 143418). 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. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2016

- -

not provided

Other:1

not provided, no classification provided

literature only

RettBASE

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

T;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.0

L;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.48

N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.047

D;D

Polyphen

0.26

B;B

Vest4

0.20

MutPred

0.32

Loss of glycosylation at P393 (P = 0.0102);.;

MVP

0.94

ClinPred

0.32

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.45

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