chrX-154030695-G-C
Variant summary
Our verdict is Uncertain significance. The variant received -2 ACMG points: 2P and 4B. BS2PS4_Moderate
This summary comes from the ClinGen Evidence Repository: The p.Ala378Gly variant has been observed in 3 individuals with Rett syndrome (PMID 16473305, 20031356, 11960578) (PS4_moderate). The p.Ala378Gly variant is observed in at least 7 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Ala378Gly variant in MECP2 is present in 3 female and 1 male individual(s) in gnomAD (0.002%) (not sufficient to meet BS1 criteria). In summary, the p.Ala378Gly variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PS4_moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270202/MONDO:0010726/036
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
Publications
- chromosome Xq28 duplication syndromeInheritance: XL Classification: DEFINITIVE Submitted by: G2P
- Rett syndromeInheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- severe neonatal-onset encephalopathy with microcephalyInheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
- syndromic X-linked intellectual disability Lubs typeInheritance: XL Classification: DEFINITIVE Submitted by: G2P
- atypical Rett syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- non-syndromic X-linked intellectual disabilityInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
- X-linked intellectual disability-psychosis-macroorchidism syndromeInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
- systemic lupus erythematosusInheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.1169C>G | p.Ala390Gly | missense_variant | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
MECP2 | NM_004992.4 | c.1133C>G | p.Ala378Gly | missense_variant | Exon 4 of 4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.1169C>G | p.Ala390Gly | missense_variant | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
MECP2 | ENST00000303391.11 | c.1133C>G | p.Ala378Gly | missense_variant | Exon 4 of 4 | 1 | NM_004992.4 | ENSP00000301948.6 |
Frequencies
GnomAD3 genomes AF: 0.0000274 AC: 3AN: 109524Hom.: 0 Cov.: 22 show subpopulations
GnomAD2 exomes AF: 0.0000172 AC: 3AN: 174908 AF XY: 0.0000159 show subpopulations
GnomAD4 exome AF: 0.00000640 AC: 7AN: 1093136Hom.: 0 Cov.: 35 AF XY: 0.00000834 AC XY: 3AN XY: 359746 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000274 AC: 3AN: 109568Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 31848 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Rett syndrome Uncertain:3Benign:1
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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 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). (PMID: 16473305, 20031356, 11960578) -
The p.Ala378Gly variant in MECP2 (NM_004992.4) is observed in at least 7 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). The p.Ala378Gly variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The highest population minor allele frequency of the p.Ala378Gly variant in MECP2 in gnomAD v4.1 is 0.00006606 in Admixed American population (not sufficient to meet BS1 criteria). In summary, the p.Ala378Gly variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). -
not provided Uncertain:1Benign:1
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This variant is associated with the following publications: (PMID: 16473305, 11960578, 26984561) -
Inborn genetic diseases Uncertain:1
The c.1133C>G (p.A378G) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to G substitution at nucleotide position 1133, causing the alanine (A) at amino acid position 378 to be replaced by a glycine (G). This variant has been detected individuals with classic Rett syndrome and Rett syndrome-like features (Milunsky, 2001; Philippe, 2006; Monnerat, 2010; Zahorakova, 2016). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
MECP2-related disorder Uncertain:1
The MECP2 c.1133C>G variant is predicted to result in the amino acid substitution p.Ala378Gly. This variant was reported in three individuals with Rett syndrome or Rett-like features (Milunsky et al. 2001. PubMed ID: 11960578; Philippe et al. 2006. PubMed ID: 16473305; Zahorakova et al. 2016. PubMed ID: 26984561). However, this variant is also reported in 0.0072% of alleles in individuals of Latino descent in gnomAD, including four heterozygotes and one hemizygote (http://gnomad.broadinstitute.org/variant/X-153296146-G-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Severe neonatal-onset encephalopathy with microcephaly Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at