rs2147065620

Variant names:

• chrX-14581370-G-A
• rs2147065620
• NM_002063.4:c.458G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R153W) has been classified as Uncertain significance.

• 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
• Publications: 2 publications found

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]

GLRA2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, X-linked, syndromic, Pilorge type

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.7002 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder, X-linked, syndromic, Pilorge type.
• 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 VariationId is 1686859.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002063.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA2	NM_002063.4	MANE Select	c.458G>A	p.Arg153Gln	missense	Exon 4 of 9	NP_002054.1	P23416-1
	GLRA2	NM_001118885.2		c.458G>A	p.Arg153Gln	missense	Exon 5 of 10	NP_001112357.1	P23416-1
	GLRA2	NM_001118886.2		c.458G>A	p.Arg153Gln	missense	Exon 4 of 9	NP_001112358.1	P23416-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA2	ENST00000218075.9	TSL:1 MANE Select	c.458G>A	p.Arg153Gln	missense	Exon 4 of 9	ENSP00000218075.4	P23416-1
	GLRA2	ENST00000355020.9	TSL:1	c.458G>A	p.Arg153Gln	missense	Exon 4 of 9	ENSP00000347123.4	P23416-2
	GLRA2	ENST00000415367.2	TSL:3	n.709G>A		non_coding_transcript_exon	Exon 4 of 9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder, X-linked, syndromic, Pilorge type (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.90		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
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs2147065620; hg19: chrX-14599492;