X-154030688-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2BP7BS1

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

2

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]

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 rank MANE Protein UniProt
MECP2NM_001110792.2 linkc.1176G>A p.Val392Val synonymous_variant Exon 3 of 3 ENST00000453960.7 NP_001104262.1 P51608-2A0A140VKC4Q59FJ6
MECP2NM_004992.4 linkc.1140G>A p.Val380Val synonymous_variant Exon 4 of 4 ENST00000303391.11 NP_004983.1 P51608-1D3YJ43Q59FJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MECP2ENST00000453960.7 linkc.1176G>A p.Val392Val synonymous_variant Exon 3 of 3 1 NM_001110792.2 ENSP00000395535.2 P51608-2
MECP2ENST00000303391.11 linkc.1140G>A p.Val380Val synonymous_variant Exon 4 of 4 1 NM_004992.4 ENSP00000301948.6 P51608-1

Frequencies

GnomAD3 genomes
AF:
0.000159
AC:
17
AN:
107229
Hom.:
0
Cov.:
21
AF XY:
0.0000334
AC XY:
1
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:
11
AN:
173247
Hom.:
0
AF XY:
0.0000644
AC XY:
4
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:
56
AN:
1091843
Hom.:
0
Cov.:
35
AF XY:
0.0000557
AC XY:
20
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:
17
AN:
107276
Hom.:
0
Cov.:
21
AF XY:
0.0000334
AC XY:
1
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.:
1
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
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

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

Other links and lift over

dbSNP: rs201711454; hg19: chrX-153296139; API