rs193922676

Variant names:

• chrX-154030677-G-A
• rs193922676
• NM_001110792.2:c.1187C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. BP5 PM6 BS2

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199482/MONDO:0010726/016

• 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
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:4
• Conservation: PhyloP100: 0.209
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• 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 rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1187C>T	p.Pro396Leu	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1151C>T	p.Pro384Leu	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1187C>T	p.Pro396Leu	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1151C>T	p.Pro384Leu	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0000183 AC: 2 AN: 109181 Hom.: 0 Cov.: 21

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

GnomAD2 exomes AF: 0.0000115 AC: 2 AN: 173513 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000596 AC: 65 AN: 1090642 Hom.: 0 Cov.: 34 AF XY: 0.0000642 AC XY: 23 AN XY: 358098

African (AFR) AF: 0.00 AC: 0 AN: 26280

American (AMR) AF: 0.000114 AC: 4 AN: 35099

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19293

East Asian (EAS) AF: 0.00 AC: 0 AN: 30169

South Asian (SAS) AF: 0.00 AC: 0 AN: 53964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37491

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3643

European-Non Finnish (NFE) AF: 0.0000703 AC: 59 AN: 838878

Other (OTH) AF: 0.0000436 AC: 2 AN: 45825

GnomAD4 genome AF: 0.0000183 AC: 2 AN: 109181 Hom.: 0 Cov.: 21 AF XY: 0.0000637 AC XY: 2 AN XY: 31415

African (AFR) AF: 0.00 AC: 0 AN: 29897

American (AMR) AF: 0.000194 AC: 2 AN: 10333

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2607

East Asian (EAS) AF: 0.00 AC: 0 AN: 3479

South Asian (SAS) AF: 0.00 AC: 0 AN: 2469

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5875

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52144

Other (OTH) AF: 0.00 AC: 0 AN: 1461

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Benign:2

Mar 27, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Oct 18, 2023

Centre for Population Genomics, CPG

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

not specified Uncertain:1

Apr 01, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 27, 2012

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Benign:1

Sep 21, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

MECP2-related disorder Benign:1

Aug 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.41
DEOGEN2	Benign	0.24	T;.
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.34	N;.
PhyloP100		0.21
PrimateAI	Uncertain	0.55	T
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	T
GERP RS		2.2
Varity_R		0.051
gMVP		0.40
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs193922676; hg19: chrX-153296128;