X-154031300-G-C

Variant names:

• chrX-154031300-G-C
• rs61754420
• NM_001110792.2:c.564C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS2 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The c.528C>G (p.Pro176=) variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - Invitae) (BS2). The silent p.Pro176= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Pro176= variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.003275% (no criteria met). In summary, the p.Pro176= variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP4, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA232982/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000035 (0 hom. 11 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:5 O:1
• Conservation: PhyloP100: 1.98

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 Likely_benign. Variant got -6 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.
• 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.564C>G	p.Pro188Pro	synonymous_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.528C>G	p.Pro176Pro	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.564C>G	p.Pro188Pro	synonymous_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.528C>G	p.Pro176Pro	synonymous_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112176 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34348

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000328 AC: 6 AN: 183200 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000735

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000346 AC: 38 AN: 1098235 Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 11 AN XY: 363589

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: 0.0000439

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112176 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Other:1

-

RettBASE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 23, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome Benign:2

Apr 22, 2024

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 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, v4 is between 0.008% and 0.03%, including 11 hemizygous (BS1). -

Oct 28, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.528C>G (p.Pro176=) variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - Invitae) (BS2). The silent p.Pro176= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). The p.Pro176= variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.003275% (no criteria met). In summary, the p.Pro176= variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP4, BP7). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Sep 09, 2018

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: 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. -

MECP2-related disorder Benign:1

Jan 11, 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
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61754420; hg19: chrX-153296751; COSMIC: COSV57652028; COSMIC: COSV57652028;