chr5-151822842-G-C

Position:

chr5-151822842-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000171.4(GLRA1):c.1181C>G(p.Pro394Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. P394L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.04

Variant links:

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

GLRA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24636844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4 linkuse as main transcript	c.1181C>G	p.Pro394Arg	missense_variant	9/9	ENST00000274576.9	NP_000162.2	P23415-2
GLRA1	NM_001146040.2 linkuse as main transcript	c.1205C>G	p.Pro402Arg	missense_variant	9/9		NP_001139512.1	P23415-1
GLRA1	NM_001292000.2 linkuse as main transcript	c.932C>G	p.Pro311Arg	missense_variant	8/8		NP_001278929.1	Q14C71
GLRA1	XM_047417105.1 linkuse as main transcript	c.1229C>G	p.Pro410Arg	missense_variant	9/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GLRA1	ENST00000274576.9 linkuse as main transcript	c.1181C>G	p.Pro394Arg	missense_variant	9/9	1	NM_000171.4	ENSP00000274576.5	P23415-2
GLRA1	ENST00000455880.2 linkuse as main transcript	c.1205C>G	p.Pro402Arg	missense_variant	9/9	1		ENSP00000411593.2	P23415-1
GLRA1	ENST00000462581.6 linkuse as main transcript	n.*939C>G		non_coding_transcript_exon_variant	8/8	1		ENSP00000430595.1	E5RJ70
GLRA1	ENST00000462581.6 linkuse as main transcript	n.*939C>G		3_prime_UTR_variant	8/8	1		ENSP00000430595.1	E5RJ70

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251406

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135862

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727212

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000481

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperekplexia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary hyperekplexia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLRA1 protein function. ClinVar contains an entry for this variant (Variation ID: 842196). This variant has not been reported in the literature in individuals affected with GLRA1-related conditions. This variant is present in population databases (rs62636581, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 394 of the GLRA1 protein (p.Pro394Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.0056

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.079

MetaRNN

Benign

0.25

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.24

Sift

Benign

0.038

D;T

Sift4G

Benign

0.16

T;T

Polyphen

0.13

B;B

Vest4

0.27

MutPred

0.42

.;Loss of glycosylation at P402 (P = 0.0047);

MVP

0.92

MPC

0.052

ClinPred

0.56

GERP RS

5.0

Varity_R

0.089

gMVP

0.61

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