X-154030790-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001110792.2(MECP2):​c.1074C>G​(p.Ser358Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 23)

Consequence

MECP2
NM_001110792.2 missense

Scores

4
7
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 4.80
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32472393).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.1074C>G p.Ser358Arg missense_variant 3/3 ENST00000453960.7 NP_001104262.1 P51608-2A0A140VKC4Q59FJ6
MECP2NM_004992.4 linkuse as main transcriptc.1038C>G p.Ser346Arg missense_variant 4/4 ENST00000303391.11 NP_004983.1 P51608-1D3YJ43Q59FJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.1074C>G p.Ser358Arg missense_variant 3/31 NM_001110792.2 ENSP00000395535.2 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.1038C>G p.Ser346Arg missense_variant 4/41 NM_004992.4 ENSP00000301948.6 P51608-1
MECP2ENST00000407218 linkuse as main transcriptc.*410C>G 3_prime_UTR_variant 4/45 ENSP00000384865.2 B5MCB4
MECP2ENST00000628176 linkuse as main transcriptc.*410C>G 3_prime_UTR_variant 5/53 ENSP00000486978.1 A0A0D9SFX7

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rett syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submittercurationCentre for Population Genomics, CPGOct 18, 2023This 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 2.0, this variant is classified as a variant of uncertain significance. -
Pathogenic, no assertion criteria providedcurationRettBASEApr 10, 2002- -
Severe neonatal-onset encephalopathy with microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 11, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MECP2 protein function. ClinVar contains an entry for this variant (Variation ID: 143310). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 346 of the MECP2 protein (p.Ser346Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.13
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
T;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.32
T;T
MetaSVM
Uncertain
0.51
D
MutationAssessor
Benign
1.6
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.99
N;N
REVEL
Uncertain
0.47
Sift
Uncertain
0.011
D;D
Sift4G
Benign
0.45
T;T
Polyphen
0.96
P;D
Vest4
0.12
MutPred
0.19
Loss of phosphorylation at S346 (P = 7e-04);.;
MVP
0.90
ClinPred
0.67
D
GERP RS
4.9
Varity_R
0.55
gMVP
0.61

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: rs61752365; hg19: chrX-153296241; API