rs796052505

Variant names:

• chr5-162095551-G-A
• rs796052505
• NM_198904.4:c.316G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-162095551-G-A
• chr5-162095551-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_198904.4(GABRG2):​c.316G>A​(p.Ala106Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 5.25

Genes affected

GABRG2 (HGNC:4087): (gamma-aminobutyric acid type A receptor subunit gamma2) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammlian brain, where it acts at GABA-A receptors, which are ligand-gated chloride channels. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene have been associated with epilepsy and febrile seizures. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a topological_domain Extracellular (size 233) in uniprot entity GBRG2_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_198904.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GABRG2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 2.9939 (below the threshold of 3.09). Trascript score misZ: 3.9213 (above the threshold of 3.09). GenCC associations: The gene is linked to epilepsy, Dravet syndrome, undetermined early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, developmental and epileptic encephalopathy, 74, febrile seizures, familial, 8, childhood epilepsy with centrotemporal spikes.
• PP5: Variant 5-162095551-G-A is Pathogenic according to our data. Variant chr5-162095551-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-162095551-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.316G>A	p.Ala106Thr	missense_variant	Exon 3 of 10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.316G>A	p.Ala106Thr	missense_variant	Exon 3 of 10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448922 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 721676

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Aug 19, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies of A106T transfected HEK293T cells demonstrated decreased GABA-evoked whole-cell currents and altered kinetic properties of GABA-A receptor currents (Shen et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29346770, 31171384, 31216405, 31087664, 30190672, 27864268, 28460589, 32901917, 32005694) -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 74 Pathogenic:4

Feb 23, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2016

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rare de novo variant also identified in 4 other patients with very similar phenotype. Pathogenic given rare de novo variant also identified in four other patients with near identical phenotype, as reported in PMID 28460589. Phenotype includes early-onset seizures, global developmental delay, intellectual disability, hypotonia, movement disorder and vision issues. -

Nov 25, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000205541.11, PMID: 28460589, 27864268, 27730413, and 31216405, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8 Pathogenic:3

Nov 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 106 of the GABRG2 protein (p.Ala106Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27730413, 27864268). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205541). 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 GABRG2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects GABRG2 function (PMID: 27864268). For these reasons, this variant has been classified as Pathogenic. -

Oct 12, 2018

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2018

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GABRG2 NM_000816.3 exon 3 p.Ala106Thr (c.316G>A): This variant has been reported in the literature in 6 individuals presenting with epilepsy and other features, 5 of whom were identified as de novo (Shen 2017 PMID:27864268; Zou 2017 PMID:28460589). This variant is absent from large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 205541). Evolutionary conservation and computational predictive tools for this variant are unclear. Additionally, in vitro functional studies support that this variant will impact the protein, disrupting channel function (Shen 2017 PMID:27864268). In summary, this variant is classified as pathogenic based on the data above. -

Febrile seizures, familial, 8;C5193074:Developmental and epileptic encephalopathy, 74 Pathogenic:2

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP2+PS4+PM6_Strong+PS3_Supporting -

Nov 11, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GABRG2 NM_000816.3 exon 3 p.Ala106Thr (c.316G>A): This variant has been reported in the literature in 6 individuals presenting with epilepsy and other features, 5 of whom were identified as de novo (Shen 2017 PMID:27864268; Zou 2017 PMID:28460589). This variant is absent from large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 205541). Evolutionary conservation and computational predictive tools for this variant are unclear. Additionally, in vitro functional studies support that this variant will impact the protein, disrupting channel function (Shen 2017 PMID:27864268). In summary, this variant is classified as pathogenic based on the data above. -

Inborn genetic diseases Pathogenic:1

Sep 26, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A106T pathogenic mutation (also known as c.316G>A), located in coding exon 3 of the GABRG2 gene, results from a G to A substitution at nucleotide position 316. The alanine at codon 106 is replaced by threonine, an amino acid with similar properties. This mutation has been reported in multiple individuals with early-onset seizures, development delay, and hypotonia (Shen D et al. Brain, 2017 01;140:49-67; Zou F et al. J. Neurogenet. May;31:30-36). Functional studies of this mutation in HEK293T cells demonstrated a reduced surface level and altered kinetic properties (Shen D et al. Brain, 2017 01;140:49-67). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-0.20	.;.;.;.;N;.;N;.;.;.;.;N;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.010	.;.;.;.;.;.;.;.;.;.;.;N;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.85	.;.;.;.;.;.;.;.;.;.;.;T;T;.
Sift4G	Benign	0.21	.;.;.;.;.;.;.;.;.;.;.;T;T;.
Polyphen		0.092, 0.11	.;.;.;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.41, 0.41
MutPred		0.47		.;.;.;.;Gain of glycosylation at A106 (P = 0.0483);.;Gain of glycosylation at A106 (P = 0.0483);.;Gain of glycosylation at A106 (P = 0.0483);.;Gain of glycosylation at A106 (P = 0.0483);Gain of glycosylation at A106 (P = 0.0483);Gain of glycosylation at A106 (P = 0.0483);Gain of glycosylation at A106 (P = 0.0483);
MVP		0.73
MPC		2.5
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.53
gMVP		0.63

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

Other links and lift over

dbSNP: rs796052505; hg19: chr5-161522557; COSMIC: COSV62721686; COSMIC: COSV62721686;