chrX-14609029-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBS2_Supporting
The NM_002063.4(GLRA2):c.754C>T(p.Arg252Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000047 in 1,063,515 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_002063.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GLRA2 | NM_002063.4 | c.754C>T | p.Arg252Cys | missense_variant | 7/9 | ENST00000218075.9 | NP_002054.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GLRA2 | ENST00000218075.9 | c.754C>T | p.Arg252Cys | missense_variant | 7/9 | 1 | NM_002063.4 | ENSP00000218075 | A1 | |
GLRA2 | ENST00000355020.9 | c.754C>T | p.Arg252Cys | missense_variant | 7/9 | 1 | ENSP00000347123 | P4 | ||
GLRA2 | ENST00000415367.2 | n.1005C>T | non_coding_transcript_exon_variant | 7/9 | 3 | |||||
GLRA2 | ENST00000443437.6 | c.*681C>T | 3_prime_UTR_variant, NMD_transcript_variant | 9/11 | 2 | ENSP00000387756 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 exomes AF: 0.00000549 AC: 1AN: 182099Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 66853
GnomAD4 exome AF: 0.00000470 AC: 5AN: 1063515Hom.: 0 Cov.: 26 AF XY: 0.00000596 AC XY: 2AN XY: 335801
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Intellectual developmental disorder, X-linked, syndromic, Pilorge type Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 26, 2022 | - - |
See cases Uncertain:1
Uncertain significance, no assertion criteria provided | research | Wangler Lab, Baylor College of Medicine | Jan 10, 2022 | Marcogliese et al., (2022) have identified 13 unrelated subjects with a variable neurodevelopmental disorder with or without autistic features. The c.754C>T results in an amino acid change of p.Arg252Cys. This variant was shown to act as Loss of Function in functional studies using Drosophila. This variant was identified in a male proband with maternal inheritance (unaffected mother). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 12, 2022 | 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. Experimental studies have shown that this missense change affects GLRA2 function (PMID: 35294868). 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 GLRA2 protein function. ClinVar contains an entry for this variant (Variation ID: 1334405). This missense change has been observed in individual(s) with GLRA2-related conditions (PMID: 35294868). This variant is present in population databases (rs748764171, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 252 of the GLRA2 protein (p.Arg252Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at