rs796052512

Positions:

• chr5-162149297-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_198904.4(GABRG2):​c.1112A>C​(p.Lys371Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.84

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRG2. . Gene score misZ: 2.9939 (greater than the threshold 3.09). Trascript score misZ: 3.9213 (greater than threshold 3.09). The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. GenCC has associacion of the gene with 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.1112A>C	p.Lys371Thr	missense_variant	8/10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.1112A>C	p.Lys371Thr	missense_variant	8/10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461656 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2018	p.Lys371Thr (AAA>ACA): c.1112 A>C in exon 8 of the GABRG2 gene (NM_000816.3) The K371T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K371T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a conserved position in the cytoplasmic loop between the third and fourth transmembrane domains of the GABRG2 protein (MacDonald et al., 2010), and a missense mutation in a nearby residue (R363Q) has been reported in association with epilepsy. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;L;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.2	.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.43
Sift	Benign	0.071	.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Benign	0.10	.;.;.;.;.;.;.;.;.;.;.;T;.;.
Polyphen		0.15, 0.087	.;.;.;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.57
MutPred		0.44		.;.;.;.;Gain of phosphorylation at K371 (P = 0.0073);.;Gain of phosphorylation at K371 (P = 0.0073);.;Gain of phosphorylation at K371 (P = 0.0073);.;Gain of phosphorylation at K371 (P = 0.0073);.;.;Gain of phosphorylation at K371 (P = 0.0073);
MVP		0.71
MPC		1.6
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.17
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

Other links and lift over

dbSNP: rs796052512; hg19: chr5-161576303;