X-14581369-C-T

Variant names:

• chrX-14581369-C-T
• rs1015303177
• NM_002063.4:c.457C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_002063.4(GLRA2):​c.457C>T​(p.Arg153Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,085,367 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic 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. R153Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: GLRA2 NM_002063.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.766
• Publications: 1 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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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, 0.979

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.457C>T	p.Arg153Trp	missense	Exon 4 of 9	NP_002054.1	P23416-1
	GLRA2	NM_001118885.2		c.457C>T	p.Arg153Trp	missense	Exon 5 of 10	NP_001112357.1	P23416-1
	GLRA2	NM_001118886.2		c.457C>T	p.Arg153Trp	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.457C>T	p.Arg153Trp	missense	Exon 4 of 9	ENSP00000218075.4	P23416-1
	GLRA2	ENST00000355020.9	TSL:1	c.457C>T	p.Arg153Trp	missense	Exon 4 of 9	ENSP00000347123.4	P23416-2
	GLRA2	ENST00000415367.2	TSL:3	n.708C>T		non_coding_transcript_exon	Exon 4 of 9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1085367 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 351499

African (AFR) AF: 0.00 AC: 0 AN: 26135

American (AMR) AF: 0.00 AC: 0 AN: 35187

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19294

East Asian (EAS) AF: 0.00 AC: 0 AN: 30152

South Asian (SAS) AF: 0.00 AC: 0 AN: 53877

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.00000361 AC: 3 AN: 830405

Other (OTH) AF: 0.00 AC: 0 AN: 45687

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.77
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.88		Gain of catalytic residue at L151 (P = 0.0423)
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.91
gMVP		0.92
Mutation Taster		=35/65	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: rs1015303177; hg19: chrX-14599491;