Variant X-14609137-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_002063.4(GLRA2):c.862G>A(p.Ala288Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,016 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 Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

GLRA2
NM_002063.4 missense

Scores

Clinical Significance

Likely 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]

GLRA2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

PP5

Variant X-14609137-G-A is Pathogenic according to our data. Variant chrX-14609137-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1334407.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA2	NM_002063.4 linkuse as main transcript	c.862G>A	p.Ala288Thr	missense_variant	7/9	ENST00000218075.9	NP_002054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA2	ENST00000218075.9 linkuse as main transcript	c.862G>A	p.Ala288Thr	missense_variant	7/9	1	NM_002063.4	ENSP00000218075	A1	P23416-1
GLRA2	ENST00000355020.9 linkuse as main transcript	c.862G>A	p.Ala288Thr	missense_variant	7/9	1		ENSP00000347123	P4	P23416-2
GLRA2	ENST00000415367.2 linkuse as main transcript	n.1113G>A		non_coding_transcript_exon_variant	7/9	3
GLRA2	ENST00000443437.6 linkuse as main transcript	c.*789G>A		3_prime_UTR_variant, NMD_transcript_variant	9/11	2		ENSP00000387756		P23416-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.18e-7

AC:

AN:

1089016

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

355474

show subpopulations

Gnomad4 AFR exome

AF:

0.0000382

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

See cases

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Wangler Lab, Baylor College of Medicine

Jan 10, 2022

Marcogliese et al., (2022) have identified 13 unrelated subjects with a variable neurodevelopmental disorder with or without autistic features. This variant (c.862C>G) results in p.Ile259Met. This change is not seen in GnomAD at this highly conserved position (PM2) and in silico models predict pathogenicity (PP3). We classify this variant to be likely pathogenic based on our cohort of affected individuals with similar phenotypes. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

.;D;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.0

.;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.3

N;N;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0080

D;D;D

Sift4G

Benign

0.12

T;T;T

Polyphen

0.97, 0.92

.;D;P

Vest4

0.62

MutPred

0.55

.;Gain of glycosylation at A288 (P = 0.1202);Gain of glycosylation at A288 (P = 0.1202);

MVP

0.96

MPC

2.2

ClinPred

0.94

GERP RS

5.4

Varity_R

0.69

gMVP

0.94

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over