chrX-14690827-C-T

Position:

chrX-14690827-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BS2

The NM_002063.4(GLRA2):c.1048C>T(p.Arg350Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000191 in 1,204,751 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. 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. R350L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000020 ( 0 hom. 7 hem. )

Consequence

GLRA2
NM_002063.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.50

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:

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

FANCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a mutagenesis_site No effect on the kinetics of inhibitory post-synaptic currents. (size 0) in uniprot entity GLRA2_HUMAN

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA2	NM_002063.4 linkuse as main transcript	c.1048C>T	p.Arg350Cys	missense_variant	8/9	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.1048C>T	p.Arg350Cys	missense_variant	8/9	1	NM_002063.4	ENSP00000218075	A1	P23416-1

Frequencies

GnomAD3 genomes

AF:

0.00000900

AC:

AN:

111118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33332

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183199

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67675

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1093633

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

359233

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000263

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000900

AC:

AN:

111118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33332

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000567

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.1048C>T (p.R350C) alteration is located in exon 8 (coding exon 8) of the GLRA2 gene. This alteration results from a C to T substitution at nucleotide position 1048, causing the arginine (R) at amino acid position 350 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual developmental disorder, X-linked, syndromic, Pilorge type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.70). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

GLRA2: PM2, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

.;D;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.68

D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.6

.;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.50

MutPred

0.57

.;Loss of disorder (P = 0.0033);Loss of disorder (P = 0.0033);

MVP

0.98

MPC

2.6

ClinPred

0.88

GERP RS

3.0

Varity_R

0.24

gMVP

0.87

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