rs211037

Positions:

• chr5-162101274-C-G
• chr5-162101274-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_198904.4(GABRG2):​c.588C>G​(p.Asn196Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N196N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38

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 5 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 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.588C>G	p.Asn196Lys	missense_variant	5/10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.588C>G	p.Asn196Lys	missense_variant	5/10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Benign	0.098
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T;D;D;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.0025	T
MutationAssessor	Benign	1.1	.;.;.;L;.;L;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	.;.;.;.;.;.;.;.;.;.;D;D;.
REVEL	Uncertain	0.40
Sift	Benign	0.19	.;.;.;.;.;.;.;.;.;.;T;T;.
Sift4G	Benign	0.18	.;.;.;.;.;.;.;.;.;.;T;T;.
Polyphen		0.37, 0.42	.;.;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.82, 0.83
MutPred		0.58		.;.;.;Gain of methylation at N196 (P = 0.0016);.;Gain of methylation at N196 (P = 0.0016);.;Gain of methylation at N196 (P = 0.0016);.;Gain of methylation at N196 (P = 0.0016);Gain of methylation at N196 (P = 0.0016);Gain of methylation at N196 (P = 0.0016);Gain of methylation at N196 (P = 0.0016);
MVP		0.79
MPC		2.7
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.69
gMVP		0.79

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: rs211037; hg19: chr5-161528280;