chrX-14609052-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_002063.4(GLRA2):​c.777C>G​(p.Ile259Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 22)

Consequence

GLRA2
NM_002063.4 missense

Scores

5
7
5

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.37
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.808
PP5
Variant X-14609052-C-G is Pathogenic according to our data. Variant chrX-14609052-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1334408.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLRA2NM_002063.4 linkuse as main transcriptc.777C>G p.Ile259Met 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.777C>G p.Ile259Met missense_variant 7/91 NM_002063.4 ENSP00000218075 A1P23416-1
GLRA2ENST00000355020.9 linkuse as main transcriptc.777C>G p.Ile259Met missense_variant 7/91 ENSP00000347123 P4P23416-2
GLRA2ENST00000415367.2 linkuse as main transcriptn.1028C>G non_coding_transcript_exon_variant 7/93
GLRA2ENST00000443437.6 linkuse as main transcriptc.*704C>G 3_prime_UTR_variant, NMD_transcript_variant 9/112 ENSP00000387756 P23416-3

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
26
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Intellectual developmental disorder, X-linked, syndromic, Pilorge type Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GLRA2-related disorder (ClinVar ID: VCV001334408). The variant has been previously reported as de novo in a similarly affected individual (PMID: 35294868). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
See cases Pathogenic:1
Likely 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. This variant (c.777C>G) results in p.Ile259Met. This change is not seen in GnomAD (PM2) and in silico models predict pathogenicity (PP3). We classify this variant to be likely pathogenic based on our cohort of affected individuals with similar phenotypes. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.56
.;D;.
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.81
D;D;D
MetaSVM
Uncertain
0.16
D
MutationAssessor
Benign
2.0
.;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-2.2
N;N;N
REVEL
Pathogenic
0.74
Sift
Benign
0.22
T;T;T
Sift4G
Benign
0.090
T;T;T
Polyphen
0.98, 0.86
.;D;P
Vest4
0.77
MutPred
0.70
.;Loss of stability (P = 0.1886);Loss of stability (P = 0.1886);
MVP
0.97
MPC
2.3
ClinPred
0.90
D
GERP RS
3.9
Varity_R
0.57
gMVP
0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-14627174; API