X-154031435-G-C

Variant names:

• chrX-154031435-G-C
• rs61748385
• NM_001110792.2:c.429C>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.393C>G (p.Ala131=) variant in MECP2 (NM_004992.3) is 0.1698% in the Ashkenazi Jewish 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 silent c.393C>G (p.Ala131=) variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.393C>G (p.Ala131=) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170296/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00013 (0 hom. 39 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 0.276

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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.429C>G	p.Ala143Ala	synonymous_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.393C>G	p.Ala131Ala	synonymous_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.429C>G	p.Ala143Ala	synonymous_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.393C>G	p.Ala131Ala	synonymous_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 26 AN: 112174 Hom.: 0 Cov.: 23 AF XY: 0.000175 AC XY: 6 AN XY: 34334

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00567

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000652

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000215 AC: 39 AN: 181568 Hom.: 0 AF XY: 0.000104 AC XY: 7 AN XY: 67304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00174

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000131 AC: 144 AN: 1097962 Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 39 AN XY: 363320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00181

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.0000903

Gnomad4 OTH exome AF: 0.000391

GnomAD4 genome AF: 0.000232 AC: 26 AN: 112174 Hom.: 0 Cov.: 23 AF XY: 0.000175 AC XY: 6 AN XY: 34334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00567

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000652

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 2

Bravo AF: 0.000181

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Mar 10, 2010

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Dec 06, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Aug 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome Benign:2

Aug 14, 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 Specifications 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). -

Oct 26, 2021

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.393C>G (p.Ala131=) variant in MECP2 (NM_004992.3) is 0.1698% in the Ashkenazi Jewish 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 silent c.393C>G (p.Ala131=) variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.393C>G (p.Ala131=) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

History of neurodevelopmental disorder Benign:1

Aug 14, 2013

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: 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. -

MECP2-related disorder Benign:1

May 19, 2021

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
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.0
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61748385; hg19: chrX-153296886; COSMIC: COSV57652119; COSMIC: COSV57652119;