rs267608504

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_Very_StrongBP7BS2_Supporting

The NM_001110792.2(MECP2):​c.639G>A​(p.Ala213=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000909 in 1,209,555 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.000090 ( 0 hom. 41 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

1
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.21
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.05390683).
BP6
Variant X-154031225-C-T is Benign according to our data. Variant chrX-154031225-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031225-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.21 with no splicing effect.
BS2
High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.639G>A p.Ala213= synonymous_variant 3/3 ENST00000453960.7 NP_001104262.1
MECP2NM_004992.4 linkuse as main transcriptc.603G>A p.Ala201= synonymous_variant 4/4 ENST00000303391.11 NP_004983.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.639G>A p.Ala213= synonymous_variant 3/31 NM_001110792.2 ENSP00000395535 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.603G>A p.Ala201= synonymous_variant 4/41 NM_004992.4 ENSP00000301948 P1P51608-1

Frequencies

GnomAD3 genomes
AF:
0.0000988
AC:
11
AN:
111288
Hom.:
0
Cov.:
23
AF XY:
0.0000597
AC XY:
2
AN XY:
33478
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00292
Gnomad AMR
AF:
0.000189
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:
0.000113
Gnomad OTH
AF:
0.000669
GnomAD3 exomes
AF:
0.0000763
AC:
14
AN:
183468
Hom.:
0
AF XY:
0.000133
AC XY:
9
AN XY:
67902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000146
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:
0.000110
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.0000901
AC:
99
AN:
1098267
Hom.:
0
Cov.:
35
AF XY:
0.000113
AC XY:
41
AN XY:
363621
show subpopulations
Gnomad4 AFR exome
AF:
0.000151
Gnomad4 AMR exome
AF:
0.000114
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:
0.000103
Gnomad4 OTH exome
AF:
0.0000868
GnomAD4 genome
AF:
0.0000988
AC:
11
AN:
111288
Hom.:
0
Cov.:
23
AF XY:
0.0000597
AC XY:
2
AN XY:
33478
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000189
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000113
Gnomad4 OTH
AF:
0.000669
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 25, 2013This 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. -
Benign, no assertion criteria providedcurationRettBASEDec 03, 2010- -
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 21, 2023- -
Rett syndrome Benign:1
Benign, criteria provided, single submittercurationCentre for Population Genomics, CPGMar 22, 2024This 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 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 3.0 (BA1). -
MECP2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 06, 2021This 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_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
0.049
DANN
Benign
0.78
DEOGEN2
Benign
0.069
T;T
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.55
T;T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.054
T;T
MetaSVM
Uncertain
0.37
D
MutationTaster
Benign
1.0
D;D;N
REVEL
Benign
0.24
Sift4G
Benign
0.11
T;T
Vest4
0.30
MVP
0.88
ClinPred
0.022
T
GERP RS
-1.2

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: rs267608504; hg19: chrX-153296676; API