rs145790362
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BP6_Very_Strong
The NM_001110792.2(MECP2):c.1469G>A(p.Arg490Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 1,209,518 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. R490R) has been classified as Likely benign.
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.1469G>A | p.Arg490Gln | missense_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.1433G>A | p.Arg478Gln | missense_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.1469G>A | p.Arg490Gln | missense_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.1433G>A | p.Arg478Gln | missense_variant | 4/4 | 1 | NM_004992.4 | P1 | |
MECP2 | ENST00000628176.2 | c.*805G>A | 3_prime_UTR_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000898 AC: 1AN: 111322Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1AN XY: 33508
GnomAD3 exomes AF: 0.00000545 AC: 1AN: 183491Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67927
GnomAD4 exome AF: 0.00000637 AC: 7AN: 1098196Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 2AN XY: 363554
GnomAD4 genome ? AF: 0.00000898 AC: 1AN: 111322Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1AN XY: 33508
ClinVar
Submissions by phenotype
Rett syndrome Benign:2
Likely benign, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Aug 14, 2023 | This 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 Likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD V3 is between 0.008% and 0.03% (BS1). The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_Supporting). - |
Likely benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Feb 18, 2022 | The p.Arg478Gln variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Arg478Gln variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). In summary, the p.Arg478Gln variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). - |
Severe neonatal-onset encephalopathy with microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces arginine with glutamine at codon 478 of the MECP2 protein (p.Arg478Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC 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: 156636). 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 20, 2023 | The c.1433G>A (p.R478Q) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a G to A substitution at nucleotide position 1433, causing the arginine (R) at amino acid position 478 to be replaced by a glutamine (Q)._x000D_ _x000D_ _x000D_ _x000D_ This variant is unlikely to be causative of Rett syndrome or MECP2 duplication syndrome; however, its contribution to the development of MECP2-related neurodevelopmental disorder is uncertain. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/205192) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.005% (1/18605) of European (Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 01, 2016 | The Arg478Gln missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is non-conservative, as a positively charged Arginine residue is replaced by an uncharged Glutamine residue, and it alters a highly conserved position in the C-terminal domain of the MECP2 protein. However, missense substitutions at nearby codons are classified as benign variants, suggesting that this region of the protein is tolerant of missense changes. Several in silico algorithms predict that Arg478Gln is likely benign, although another model suggests it may be damaging to protein structure/function. Therefore, based on the available information it is currently unclear whether Arg478Gln is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s). - |
Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not specified Benign:1
Benign, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at