X-14581319-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5

The NM_002063.4(GLRA2):c.407A>G(p.Asn136Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,203,535 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Consequence

GLRA2
NM_002063.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.23

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS1

Transcript NM_002063.4 (GLRA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a topological_domain Extracellular (size 228) in uniprot entity GLRA2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002063.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant X-14581319-A-G is Pathogenic according to our data. Variant chrX-14581319-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1686857.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA2	NM_002063.4 linkuse as main transcript	c.407A>G	p.Asn136Ser	missense_variant	4/9	ENST00000218075.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA2	ENST00000218075.9 linkuse as main transcript	c.407A>G	p.Asn136Ser	missense_variant	4/9	1	NM_002063.4	A1	P23416-1
GLRA2	ENST00000355020.9 linkuse as main transcript	c.407A>G	p.Asn136Ser	missense_variant	4/9	1		P4	P23416-2
GLRA2	ENST00000415367.2 linkuse as main transcript	n.658A>G		non_coding_transcript_exon_variant	4/9	3
GLRA2	ENST00000443437.6 linkuse as main transcript	c.*334A>G		3_prime_UTR_variant, NMD_transcript_variant	6/11	2			P23416-3

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111649

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33831

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.16e-7

AC:

AN:

1091886

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

357464

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111649

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33831

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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 provided

literature only

OMIM

Apr 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

Cadd

Pathogenic

Dann

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.98, 1.0

.;D;D;.

Vest4

0.93

MutPred

0.91

.;Gain of glycosylation at N136 (P = 0.0342);Gain of glycosylation at N136 (P = 0.0342);.;

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

5.6

Varity_R

0.89

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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