rs1557137821

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001110792.2(MECP2):​c.286C>T​(p.Arg96Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,097,327 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

12
3
2

Clinical Significance

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

Conservation

PhyloP100: 6.03
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.286C>T p.Arg96Trp missense_variant 2/3 ENST00000453960.7 NP_001104262.1
MECP2NM_004992.4 linkuse as main transcriptc.250C>T p.Arg84Trp missense_variant 3/4 ENST00000303391.11 NP_004983.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.286C>T p.Arg96Trp missense_variant 2/31 NM_001110792.2 ENSP00000395535 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.250C>T p.Arg84Trp missense_variant 3/41 NM_004992.4 ENSP00000301948 P1P51608-1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1097327
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
362753
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000238
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
24

ClinVar

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

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2022This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 84 of the MECP2 protein (p.Arg84Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 536586). 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 expected to disrupt MECP2 protein function. In 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 18, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12843318, 21831886) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.64
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D;.;T;T;T;T;T
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Benign
0.90
L;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-3.7
D;D;.;.;.;.;.
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D;D;.;.;.;.;.
Sift4G
Uncertain
0.027
D;D;D;D;.;D;D
Polyphen
1.0
D;D;.;.;.;.;.
Vest4
0.81
MutPred
0.30
Gain of ubiquitination at K82 (P = 0.0222);.;Gain of ubiquitination at K82 (P = 0.0222);.;Gain of ubiquitination at K82 (P = 0.0222);.;.;
MVP
1.0
ClinPred
0.99
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.72
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1557137821; hg19: chrX-153297785; COSMIC: COSV57657855; COSMIC: COSV57657855; API