X-14607193-G-C

Variant names:

• chrX-14607193-G-C
• NM_002063.4:c.640G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002063.4(GLRA2):​c.640G>C​(p.Glu214Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLRA2 NM_002063.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Extracellular (size 228) in uniprot entity GLRA2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002063.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA2	NM_002063.4	c.640G>C	p.Glu214Gln	missense_variant	Exon 6 of 9	ENST00000218075.9	NP_002054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA2	ENST00000218075.9	c.640G>C	p.Glu214Gln	missense_variant	Exon 6 of 9	1	NM_002063.4	ENSP00000218075.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder, X-linked, syndromic, Pilorge type Uncertain:1

Oct 18, 2024

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant in exon 6 of the GLRA2 gene that results in the amino acid substitution of Glutamine for Glutamic acid at codon 214 (p.Glu214Gln) was detected. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomAD (v2.1), and topmed databases. The in silico predictions of the variant are damaging by SIFT and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Uncertain	0.0043	D
MutationAssessor	Benign	1.7	.;L;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.095	T;D;D;D
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.099, 0.012	.;B;B;.
Vest4		0.27
MutPred		0.52		.;Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;
MVP		0.92
MPC		2.1
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.51
gMVP		0.61

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-14625315;