X-14609162-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_002063.4(GLRA2):c.887C>T(p.Thr296Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 22)
Consequence
GLRA2
NM_002063.4 missense
NM_002063.4 missense
Scores
16
1
Clinical Significance
Conservation
PhyloP100: 7.83
Genes affected
GLRA2 (HGNC:4327): (glycine receptor alpha 2) The glycine receptor consists of two subunits, alpha and beta, and acts as a pentamer. The protein encoded by this gene is an alpha subunit and can bind strychnine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
Variant X-14609162-C-T is Pathogenic according to our data. Variant chrX-14609162-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 810510.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GLRA2 | NM_002063.4 | c.887C>T | p.Thr296Met | 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.887C>T | p.Thr296Met | missense_variant | 7/9 | 1 | NM_002063.4 | ENSP00000218075 | A1 | |
GLRA2 | ENST00000355020.9 | c.887C>T | p.Thr296Met | missense_variant | 7/9 | 1 | ENSP00000347123 | P4 | ||
GLRA2 | ENST00000415367.2 | n.1138C>T | non_coding_transcript_exon_variant | 7/9 | 3 | |||||
GLRA2 | ENST00000443437.6 | c.*814C>T | 3_prime_UTR_variant, NMD_transcript_variant | 9/11 | 2 | ENSP00000387756 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 02, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 810510). This missense change has been observed in individual(s) with GLRA2-related conditions (PMID: 28135719, 35294868). In at least one individual the variant was observed to be de novo. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 296 of the GLRA2 protein (p.Thr296Met). - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2020 | - - |
Intellectual developmental disorder, X-linked, syndromic, Pilorge type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 26, 2022 | - - |
See cases Pathogenic:1
Pathogenic, 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 p.Thr296Met was shown to act as a Gain of Function in functional studies using Drosophila. This variant reoccurred as a de novo in six independent female probands. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;D
Vest4
MutPred
0.81
.;Loss of glycosylation at T296 (P = 0.0618);Loss of glycosylation at T296 (P = 0.0618);
MVP
MPC
2.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at