X-14581370-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5

The NM_002063.4(GLRA2):c.458G>A(p.Arg153Gln) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLRA2 NM_002063.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P: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 Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_002063.4 (GLRA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a topological_domain Extracellular (size 228) in uniprot entity GLRA2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002063.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-14581370-G-A is Pathogenic according to our data. Variant chrX-14581370-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1686859.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-14581370-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA2	NM_002063.4	c.458G>A	p.Arg153Gln	missense_variant	4/9	ENST00000218075.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA2	ENST00000218075.9	c.458G>A	p.Arg153Gln	missense_variant	4/9	1	NM_002063.4	A1
GLRA2	ENST00000355020.9	c.458G>A	p.Arg153Gln	missense_variant	4/9	1		P4
GLRA2	ENST00000415367.2	n.709G>A		non_coding_transcript_exon_variant	4/9	3
GLRA2	ENST00000443437.6	c.*385G>A		3_prime_UTR_variant, NMD_transcript_variant	6/11	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 26, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;T
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.82
MutPred		0.90		.;Loss of MoRF binding (P = 0.0139);Loss of MoRF binding (P = 0.0139);.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.68
gMVP		0.91

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-14599492;