chrX-14581370-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_ModeratePM2PP3_StrongPP5

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

Scores

10
6
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.90
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1
Transcript NM_002063.4 (GLRA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
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 Protein UniProt
GLRA2NM_002063.4 linkuse as main transcriptc.458G>A p.Arg153Gln missense_variant 4/9 ENST00000218075.9 NP_002054.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLRA2ENST00000218075.9 linkuse as main transcriptc.458G>A p.Arg153Gln missense_variant 4/91 NM_002063.4 ENSP00000218075 A1P23416-1
GLRA2ENST00000355020.9 linkuse as main transcriptc.458G>A p.Arg153Gln missense_variant 4/91 ENSP00000347123 P4P23416-2
GLRA2ENST00000415367.2 linkuse as main transcriptn.709G>A non_coding_transcript_exon_variant 4/93
GLRA2ENST00000443437.6 linkuse as main transcriptc.*385G>A 3_prime_UTR_variant, NMD_transcript_variant 6/112 ENSP00000387756 P23416-3

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
LINK: link

Submissions by phenotype

Intellectual developmental disorder, X-linked, syndromic, Pilorge type Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 26, 2022- -

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
DEOGEN2
Pathogenic
0.83
.;D;.;.
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
MutationAssessor
Uncertain
2.9
.;M;M;.
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; API