rs1060501888

Variant names:

• chr5-162149246-G-T
• rs1060501888
• NM_198904.4:c.1061G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_198904.4(GABRG2):​c.1061G>T​(p.Gly354Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.66
• Publications: 2 publications found

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]

GABRG2 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 74

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• febrile seizures, familial, 8

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• self-limited epilepsy with centrotemporal spikes

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant 5-162149246-G-T is Pathogenic according to our data. Variant chr5-162149246-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 408211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.1061G>T	p.Gly354Val	missense_variant	Exon 8 of 10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.1061G>T	p.Gly354Val	missense_variant	Exon 8 of 10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8 Pathogenic:1

Apr 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with valine at codon 354 of the GABRG2 protein (p.Gly354Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been reported to be de novo in an individual affected with epilepsy (Invitae database). This variant is not present in population databases (ExAC no frequency). -

Developmental and epileptic encephalopathy, 74 Pathogenic:1

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant, NM_000816.3(GABRG2):c.1061G>T, has been identified in exon 8 of 9 of the GABRG2 gene. The variant is predicted to result in a major amino acid change from glycine to valine at position 354 of the protein (NP_000807.2(GABRG2):p.(Gly354Val)). The glycine residue at this position has moderate conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD) and is located within a region of high missense constraint (Decipher). The variant has been previously described as likely pathogenic (ClinVar) in an individual affected with epilepsy. Analysis of parental samples indicated that this variant is de novo. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.68	.;.;.;.;N;.;N;.;.;.;.;.;.;.
PhyloP100		5.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0020	.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.88, 0.95	.;.;.;.;P;.;P;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.64		.;.;.;.;Gain of catalytic residue at G354 (P = 0.0505);.;Gain of catalytic residue at G354 (P = 0.0505);.;Gain of catalytic residue at G354 (P = 0.0505);.;Gain of catalytic residue at G354 (P = 0.0505);.;.;Gain of catalytic residue at G354 (P = 0.0505);
MVP		0.92
MPC		2.8
ClinPred		0.84	D
GERP RS		5.6
Varity_R		0.72
gMVP		0.98
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060501888; hg19: chr5-161576252;