rs41311629

Positions:

• chr5-162102625-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000414552.6(GABRG2):​c.703G>T​(p.Gly235Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 453,378 control chromosomes in the GnomAD database, including 2,565 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G235G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.11 (912 hom., cov: 32)
  • Exomes 𝑓: 0.10 (1653 hom.)
• Consequence: GABRG2 ENST00000414552.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.504

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GABRG2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018987358).
• BP6: Variant 5-162102625-G-T is Benign according to our data. Variant chr5-162102625-G-T is described in ClinVar as [Benign]. Clinvar id is 585904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG2	NM_198904.4	c.632-1264G>T		intron_variant		ENST00000639213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG2	ENST00000639213.2	c.632-1264G>T		intron_variant		1	NM_198904.4	A1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16230 AN: 151778 Hom.: 912 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0883

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0641

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.0969 AC: 12418 AN: 128194 Hom.: 639 AF XY: 0.0983 AC XY: 6897 AN XY: 70192

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.0666

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0656

Gnomad SAS exome AF: 0.0977

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.101 AC: 30468 AN: 301482 Hom.: 1653 Cov.: 0 AF XY: 0.102 AC XY: 17545 AN XY: 171808

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0661

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.0656

Gnomad4 SAS exome AF: 0.0979

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.0990

GnomAD4 genome AF: 0.107 AC: 16237 AN: 151896 Hom.: 912 Cov.: 32 AF XY: 0.106 AC XY: 7892 AN XY: 74198

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0882

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.0643

Gnomad4 SAS AF: 0.0958

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.102

Alfa AF: 0.108 Hom.: 160

Bravo AF: 0.104

TwinsUK AF: 0.104 AC: 386

ALSPAC AF: 0.105 AC: 405

ExAC AF: 0.0864 AC: 1247

Asia WGS AF: 0.0840 AC: 293 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.0
DANN	Benign	0.24
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.29	N;.
REVEL	Benign	0.047
Sift	Uncertain	0.0060	D;.
Sift4G	Benign	0.064	T;.
Vest4		0.060
MPC		1.4
ClinPred		0.0020	T
GERP RS		-0.45
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41311629; hg19: chr5-161529631; COSMIC: COSV62718850; COSMIC: COSV62718850;