rs146107517

Variant names:

• chrX-154032209-G-T
• rs146107517
• NM_001110792.2:c.411C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ile125= variant in MECP2 (NM_004992) is 0.394% in South Asian 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.Ile125= variant is observed in at least 2 unaffected individuals (PMID 11055898, 20479760, RettBASE proband id 4623, 4624) (BS2). In summary, the p.Ile125= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211309/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., 18 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (2 hom. 429 hem.)
• Consequence: MECP2 NM_001110792.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003851
• Clinical Significance: Benign reviewed by expert panel U:1 B:14
• Conservation: PhyloP100: 7.63
• Publications: 1 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: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.411C>A	p.Ile137Ile	splice_region synonymous	Exon 2 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.375C>A	p.Ile125Ile	splice_region synonymous	Exon 3 of 4	NP_004983.1
	MECP2	NM_001386137.1		c.-186C>A		splice_region	Exon 4 of 6	NP_001373066.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.411C>A	p.Ile137Ile	splice_region synonymous	Exon 2 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.375C>A	p.Ile125Ile	splice_region synonymous	Exon 3 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.375C>A	p.Ile125Ile	splice_region synonymous	Exon 3 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.000700 AC: 79 AN: 112933 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00469

Gnomad FIN AF: 0.000159

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000939 AC: 172 AN: 183190 AF XY: 0.00123

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00267

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.000918

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00107 AC: 1168 AN: 1092411 Hom.: 2 Cov.: 30 AF XY: 0.00120 AC XY: 429 AN XY: 358097

African (AFR) AF: 0.0000761 AC: 2 AN: 26297

American (AMR) AF: 0.0000852 AC: 3 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00274 AC: 53 AN: 19351

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00361 AC: 195 AN: 53969

European-Finnish (FIN) AF: 0.0000988 AC: 4 AN: 40497

Middle Eastern (MID) AF: 0.000486 AC: 2 AN: 4113

European-Non Finnish (NFE) AF: 0.00103 AC: 859 AN: 836884

Other (OTH) AF: 0.00109 AC: 50 AN: 45919

GnomAD4 genome AF: 0.000699 AC: 79 AN: 112987 Hom.: 1 Cov.: 24 AF XY: 0.000512 AC XY: 18 AN XY: 35141

African (AFR) AF: 0.0000320 AC: 1 AN: 31216

American (AMR) AF: 0.000279 AC: 3 AN: 10753

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

South Asian (SAS) AF: 0.00470 AC: 13 AN: 2766

European-Finnish (FIN) AF: 0.000159 AC: 1 AN: 6270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00107 AC: 57 AN: 53295

Other (OTH) AF: 0.00 AC: 0 AN: 1541

Alfa AF: 0.00103 Hom.: 14

Bravo AF: 0.000578

EpiCase AF: 0.00131

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Nov 01, 2011

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Apr 16, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 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.

Sep 04, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 18, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 25, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 09, 2007

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Uncertain:1 Benign:2

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Rett syndrome Benign:2

May 10, 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 p.Ile125= variant in MECP2 (NM_004992) is 0.394% in South Asian 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.Ile125= variant is observed in at least 2 unaffected individuals (PMID 11055898, 20479760, RettBASE proband id 4623, 4624) (BS2). In summary, the p.Ile125= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2).

Mar 08, 2024

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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, 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 3.0 (BA1).

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

History of neurodevelopmental disorder Benign:1

Aug 19, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Synonymous alterations with insufficient evidence to classify as benign

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.79
PhyloP100		7.6
PromoterAI		-0.10	Neutral
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.078
SpliceAI score (max)		0.020		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: rs146107517; hg19: chrX-153297660;