Variant rs768735440 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_002063.4(GLRA2):c.1334G>A(p.Arg445Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000997 in 1,203,603 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.0000082 ( 0 hom. 1 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:

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 1 ACMG points.

PP5

Variant X-14730460-G-A is Pathogenic according to our data. Variant chrX-14730460-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1334411.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA2	NM_002063.4 link	c.1334G>A	p.Arg445Gln	missense_variant	Exon 9 of 9	ENST00000218075.9	NP_002054.1	P23416-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA2	ENST00000218075.9 link	c.1334G>A	p.Arg445Gln	missense_variant	Exon 9 of 9	1	NM_002063.4	ENSP00000218075.4		P23416-1

Frequencies

GnomAD3 genomes

AF:

0.0000275

AC:

AN:

109251

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

31605

show subpopulations

Gnomad AFR

AF:

0.0000334

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000987

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183303

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67795

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1094302

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

359810

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00000954

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000274

AC:

AN:

109301

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

31665

show subpopulations

Gnomad4 AFR

AF:

0.0000333

Gnomad4 AMR

AF:

0.0000986

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

See cases

Pathogenic:1

Jan 10, 2022

Wangler Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Marcogliese et al., (2022) have identified 13 unrelated subjects with a variable neurodevelopmental disorder with or without autistic features. This variant (c.1134G>A) results in p.Arg445Gln. This change has a very low allele frequency in GnomAD (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

Benign

0.20

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

.;T;.

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.66

D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.6

.;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.1

N;N;N

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.083

T;T;T

Polyphen

0.99, 1.0

.;D;D

Vest4

0.64

MVP

0.97

MPC

2.5

ClinPred

0.83

GERP RS

4.8

Varity_R

0.56

gMVP

0.82

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