rs201711454

Positions:

chrX-154030688-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP7BS1BS2

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

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: -0.0780

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1176G>A	p.Val392Val	synonymous_variant	3/3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 linkuse as main transcript	c.1140G>A	p.Val380Val	synonymous_variant	4/4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1176G>A	p.Val392Val	synonymous_variant	3/3	1	NM_001110792.2	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1140G>A	p.Val380Val	synonymous_variant	4/4	1	NM_004992.4	ENSP00000301948.6	P51608-1
MECP2	ENST00000407218 linkuse as main transcript	c.*512G>A		3_prime_UTR_variant	4/4	5		ENSP00000384865.2	B5MCB4
MECP2	ENST00000628176 linkuse as main transcript	c.*512G>A		3_prime_UTR_variant	5/5	3		ENSP00000486978.1	A0A0D9SFX7

Frequencies

GnomAD3 genomes

AF:

0.000159

AC:

AN:

107229

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

29921

show subpopulations

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:

AN:

173247

Hom.:

AF XY:

0.0000644

AC XY:

AN XY:

62135

show subpopulations

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:

AN:

1091843

Hom.:

Cov.:

AF XY:

0.0000557

AC XY:

AN XY:

358965

show subpopulations

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:

AN:

107276

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

29978

show subpopulations

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.:

Bravo

AF:

0.000419

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2018	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

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Mar 26, 2021

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2018

- -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2019

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over