5-162142202-A-G

Position:

• chr5-162142202-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_198904.4(GABRG2):​c.808A>G​(p.Arg270Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.58

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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). GenCC has associacion of 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 5-162142202-A-G is Pathogenic according to our data. Variant chr5-162142202-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205563.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.808A>G	p.Arg270Gly	missense_variant	7/10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.808A>G	p.Arg270Gly	missense_variant	7/10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2014

p.Arg270Gly (AGA>GGA): c.808 A>G in exon 7 of the GABRG2 gene (NM_000816.3) The R270G 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 R270G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, other missense mutations in nearby residues have not been reported. Therefore, based on the currently available information, it is unclear whether the R270G variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;.;.;.;H;.;H;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.4	.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0020	.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		1.0, 1.0	.;.;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.97
MutPred		0.95		.;.;.;.;Gain of methylation at R271 (P = 0.0367);.;Gain of methylation at R271 (P = 0.0367);.;Gain of methylation at R271 (P = 0.0367);.;Gain of methylation at R271 (P = 0.0367);.;.;Gain of methylation at R271 (P = 0.0367);
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		1.0

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: rs796052520; hg19: chr5-161569208;