X-14609052-C-G

Position:

• chrX-14609052-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.37

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 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
GLRA2	NM_002063.4	c.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
GLRA2	ENST00000218075.9	c.777C>G	p.Ile259Met	missense_variant	7/9	1	NM_002063.4	ENSP00000218075	A1
GLRA2	ENST00000355020.9	c.777C>G	p.Ile259Met	missense_variant	7/9	1		ENSP00000347123	P4
GLRA2	ENST00000415367.2	n.1028C>G		non_coding_transcript_exon_variant	7/9	3
GLRA2	ENST00000443437.6	c.*704C>G		3_prime_UTR_variant, NMD_transcript_variant	9/11	2		ENSP00000387756

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

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

The 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 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. 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;