rs61752387

Variant names:

• chrX-154030702-G-A
• rs61752387
• NM_001110792.2:c.1162C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.1126C>T, p.(Pro376Ser) variant in MECP2(NM_004992.4) is 0.13% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.(Pro376Ser) variant is observed in at least 2 unaffected individuals (PMID 10944854, PMID 14560307, RettBASE) (BS1). In summary, the p.(Pro376Ser) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA148292/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 24 hem., cov: 22)
  • Exomes 𝑓: 0.0015 (0 hom. 537 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:15
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1162C>T	p.Pro388Ser	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1126C>T	p.Pro376Ser	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.1162C>T	p.Pro388Ser	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1126C>T	p.Pro376Ser	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 112 AN: 109987 Hom.: 0 Cov.: 22 AF XY: 0.000745 AC XY: 24 AN XY: 32209

Gnomad AFR AF: 0.000596

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00172

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000335

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000998 AC: 176 AN: 176306 Hom.: 0 AF XY: 0.000976 AC XY: 62 AN XY: 63496

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00292

Gnomad SAS exome AF: 0.000268

Gnomad FIN exome AF: 0.000813

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00152 AC: 1661 AN: 1094648 Hom.: 0 Cov.: 35 AF XY: 0.00149 AC XY: 537 AN XY: 360858

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000855

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00196

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.000609

Gnomad4 NFE exome AF: 0.00176

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00102 AC: 112 AN: 110036 Hom.: 0 Cov.: 22 AF XY: 0.000744 AC XY: 24 AN XY: 32268

Gnomad4 AFR AF: 0.000595

Gnomad4 AMR AF: 0.000192

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00172

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000335

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00157 Hom.: 58

Bravo AF: 0.000929

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00107 AC: 4

ESP6500EA AF: 0.00152 AC: 10

ExAC AF: 0.000776 AC: 94

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:10

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2020

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 16, 2015

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2010

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Mar 18, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Rett syndrome Uncertain:1 Benign:3

Jul 06, 2023

Centre for Population Genomics, CPG

Significance: 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 to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0 , this variant is classified as Benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign, for Rett syndrome, in X-linked Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BS4 => Lack of segregation in affected members of a family (PMID:12567420) (PMID:12161600). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). -

Apr 28, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the c.1126C>T, p.(Pro376Ser) variant in MECP2 (NM_004992.4) is 0.13% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.(Pro376Ser) variant is observed in at least 2 unaffected individuals (PMID 10944854, PMID 14560307, RettBASE) (BS1). In summary, the p.(Pro376Ser) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 12, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.25	T;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.070	N;N
REVEL	Uncertain	0.51
Sift	Benign	0.20	T;T
Sift4G	Benign	0.073	T;T
Polyphen		0.0	B;B
Vest4		0.063
MVP		0.76
ClinPred		0.00039	T
GERP RS		3.2
Varity_R		0.042
gMVP		0.30

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

Other links and lift over

dbSNP: rs61752387; hg19: chrX-153296153; COSMIC: COSV99066745; COSMIC: COSV99066745;