X-154030688-C-T

Variant names:

• chrX-154030688-C-T
• rs201711454
• NM_001110792.2:c.1176G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2 BP7 BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Val380= variant in MECP2 is 0.018% in Latino sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Val380= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Val380= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Val380= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA208360/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000051 (0 hom. 20 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: -0.0780

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 -9 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.1176G>A	p.Val392Val	synonymous_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1140G>A	p.Val380Val	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.1176G>A	p.Val392Val	synonymous_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1140G>A	p.Val380Val	synonymous_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.000159 AC: 17 AN: 107229 Hom.: 0 Cov.: 21 AF XY: 0.0000334 AC XY: 1 AN XY: 29921

Gnomad AFR AF: 0.0000342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000292

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000194

Gnomad OTH AF: 0.00210

GnomAD3 exomes AF: 0.0000635 AC: 11 AN: 173247 Hom.: 0 AF XY: 0.0000644 AC XY: 4 AN XY: 62135

Gnomad AFR exome AF: 0.0000848

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000538

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000521

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000513 AC: 56 AN: 1091843 Hom.: 0 Cov.: 35 AF XY: 0.0000557 AC XY: 20 AN XY: 358965

Gnomad4 AFR exome AF: 0.0000381

Gnomad4 AMR exome AF: 0.000257

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.0000262

Gnomad4 NFE exome AF: 0.0000417

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000158 AC: 17 AN: 107276 Hom.: 0 Cov.: 21 AF XY: 0.0000334 AC XY: 1 AN XY: 29978

Gnomad4 AFR AF: 0.0000341

Gnomad4 AMR AF: 0.00108

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000293

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000194

Gnomad4 OTH AF: 0.00207

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.000419

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Jun 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2017

GeneDx

Significance: Likely 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 06, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MECP2 c.1140G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no effect on splicing. The variant allele was found at a frequency of 6.5e-05 in 169949 control chromosomes, including 4 hemizygotes. The observed variant frequency is approximately 8-fold above the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1140G>A in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Rett syndrome Benign:1

Mar 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 p.Val380= variant in MECP2 is 0.018% in Latino sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Val380= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Val380= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Val380= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP7). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MECP2-related disorder Benign:1

Nov 21, 2019

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	-0.86
CADD	Benign	0.17
DANN	Benign	0.48

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: rs201711454; hg19: chrX-153296139;