X-14609029-C-T

Variant names:

• chrX-14609029-C-T
• rs748764171
• NM_002063.4:c.754C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PP2 PP3_Strong BS2_Supporting

The NM_002063.4(GLRA2):​c.754C>T​(p.Arg252Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000047 in 1,063,515 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000047 (0 hom. 2 hem.)
• Consequence: GLRA2 NM_002063.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 2.34
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• 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, 0.966
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.754C>T	p.Arg252Cys	missense	Exon 7 of 9	NP_002054.1	P23416-1
	GLRA2	NM_001118885.2		c.754C>T	p.Arg252Cys	missense	Exon 8 of 10	NP_001112357.1	P23416-1
	GLRA2	NM_001118886.2		c.754C>T	p.Arg252Cys	missense	Exon 7 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.754C>T	p.Arg252Cys	missense	Exon 7 of 9	ENSP00000218075.4	P23416-1
	GLRA2	ENST00000355020.9	TSL:1	c.754C>T	p.Arg252Cys	missense	Exon 7 of 9	ENSP00000347123.4	P23416-2
	GLRA2	ENST00000415367.2	TSL:3	n.1005C>T		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182099 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000470 AC: 5 AN: 1063515 Hom.: 0 Cov.: 26 AF XY: 0.00000596 AC XY: 2 AN XY: 335801

African (AFR) AF: 0.00 AC: 0 AN: 25682

American (AMR) AF: 0.00 AC: 0 AN: 35039

Ashkenazi Jewish (ASJ) AF: 0.0000523 AC: 1 AN: 19129

East Asian (EAS) AF: 0.00 AC: 0 AN: 30045

South Asian (SAS) AF: 0.00 AC: 0 AN: 53338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4057

European-Non Finnish (NFE) AF: 0.00000370 AC: 3 AN: 810840

Other (OTH) AF: 0.0000223 AC: 1 AN: 44889

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Intellectual developmental disorder, X-linked, syndromic, Pilorge type (2)
-	1	-	not provided (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		2.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.77		Loss of catalytic residue at R252 (P = 0.0255)
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.99
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs748764171; hg19: chrX-14627151; COSMIC: COSV105099878; COSMIC: COSV105099878;