rs372500343

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7BA1BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.54C>G p.Leu18= variant in MECP2 (NM_004992.1) is 0.042% in the African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Leu18= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.54C>G p.Leu18= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA243345/MONDO:0010726/032

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 1 hem., cov: 24)
Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

MECP2
NM_001316337.2 5_prime_UTR_premature_start_codon_gain

Scores

2

Clinical Significance

Benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 0.568
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 -10 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.
BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MECP2NM_001110792.2 linkc.90C>G p.Leu30Leu synonymous_variant 2/3 ENST00000453960.7 NP_001104262.1 P51608-2A0A140VKC4Q59FJ6
MECP2NM_004992.4 linkc.54C>G p.Leu18Leu synonymous_variant 3/4 ENST00000303391.11 NP_004983.1 P51608-1D3YJ43Q59FJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MECP2ENST00000453960.7 linkc.90C>G p.Leu30Leu synonymous_variant 2/31 NM_001110792.2 ENSP00000395535.2 P51608-2
MECP2ENST00000303391.11 linkc.54C>G p.Leu18Leu synonymous_variant 3/41 NM_004992.4 ENSP00000301948.6 P51608-1

Frequencies

GnomAD3 genomes
AF:
0.0000622
AC:
7
AN:
112613
Hom.:
0
Cov.:
24
AF XY:
0.0000288
AC XY:
1
AN XY:
34747
show subpopulations
Gnomad AFR
AF:
0.000226
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000336
AC:
6
AN:
178410
Hom.:
0
AF XY:
0.0000152
AC XY:
1
AN XY:
65586
show subpopulations
Gnomad AFR exome
AF:
0.000460
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000366
AC:
4
AN:
1094125
Hom.:
0
Cov.:
31
AF XY:
0.00000277
AC XY:
1
AN XY:
361283
show subpopulations
Gnomad4 AFR exome
AF:
0.000152
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000621
AC:
7
AN:
112667
Hom.:
0
Cov.:
24
AF XY:
0.0000287
AC XY:
1
AN XY:
34811
show subpopulations
Gnomad4 AFR
AF:
0.000226
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000793

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 27, 2015- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 23, 2020- -
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 29, 2024- -
Rett syndrome Benign:1
Benign, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelJun 15, 2023The allele frequency of the c.54C>G p.Leu18= variant in MECP2 (NM_004992.1) is 0.042% in the African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Leu18= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.54C>G p.Leu18= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). -
MECP2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 24, 2023This 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
7.6
DANN
Benign
0.79
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

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

Other links and lift over

dbSNP: rs372500343; hg19: chrX-153297981; API