X-14609162-C-T

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

Scores

16
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.83
Variant links:
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
GLRA2NM_002063.4 linkuse as main transcriptc.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
GLRA2ENST00000218075.9 linkuse as main transcriptc.887C>T p.Thr296Met missense_variant 7/91 NM_002063.4 ENSP00000218075 A1P23416-1
GLRA2ENST00000355020.9 linkuse as main transcriptc.887C>T p.Thr296Met missense_variant 7/91 ENSP00000347123 P4P23416-2
GLRA2ENST00000415367.2 linkuse as main transcriptn.1138C>T non_coding_transcript_exon_variant 7/93
GLRA2ENST00000443437.6 linkuse as main transcriptc.*814C>T 3_prime_UTR_variant, NMD_transcript_variant 9/112 ENSP00000387756 P23416-3

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
28
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 02, 2023This 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2020- -
Intellectual developmental disorder, X-linked, syndromic, Pilorge type Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 26, 2022- -
See cases Pathogenic:1
Pathogenic, no assertion criteria providedresearchWangler Lab, Baylor College of MedicineJan 10, 2022Marcogliese 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
.;D;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
3.6
.;H;H
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-5.7
D;D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.88
MutPred
0.81
.;Loss of glycosylation at T296 (P = 0.0618);Loss of glycosylation at T296 (P = 0.0618);
MVP
0.98
MPC
2.4
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.86
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1601761445; hg19: chrX-14627284; COSMIC: COSV54336236; COSMIC: COSV54336236; API