X-14604316-C-G

Variant names:

• chrX-14604316-C-G
• NM_002063.4:c.496C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002063.4(GLRA2):​c.496C>G​(p.Leu166Val) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GLRA2 NM_002063.4 missense, splice_region
• Scores: Splicing: ADA: 0.9430
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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.

• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA2	NM_002063.4	c.496C>G	p.Leu166Val	missense_variant, splice_region_variant	Exon 5 of 9	ENST00000218075.9	NP_002054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA2	ENST00000218075.9	c.496C>G	p.Leu166Val	missense_variant, splice_region_variant	Exon 5 of 9	1	NM_002063.4	ENSP00000218075.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.1	.;M;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D;D;D;T
Sift4G	Benign	0.073	T;D;D;T
Polyphen		0.98, 0.27	.;D;B;.
Vest4		0.55
MutPred		0.73		.;Loss of stability (P = 0.1077);Loss of stability (P = 0.1077);.;
MVP		1.0
MPC		1.8
ClinPred		0.95	D
GERP RS		3.9
Varity_R		0.48
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 1

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-14622438;