rs41311629

Variant names:

• chr5-162102625-G-T
• rs41311629
• ENST00000414552.6:c.703G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198903.2(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. 14/19 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 NM_198903.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.504
• Publications: 3 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: G2P, Ambry Genetics, 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: Benign. The variant received -20 ACMG points.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198903.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	NM_198904.4	MANE Select	c.632-1264G>T		intron	N/A	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.703G>T	p.Gly235Cys	missense	Exon 6 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.703G>T	p.Gly235Cys	missense	Exon 6 of 10	NP_001362272.1	A0A1X7SBZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	ENST00000414552.6	TSL:1	c.703G>T	p.Gly235Cys	missense	Exon 6 of 11	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.632-1264G>T		intron	N/A	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000639111.2	TSL:1	c.632-1264G>T		intron	N/A	ENSP00000492125.2	P18507-1

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

GnomAD2 exomes AF: 0.0969 AC: 12418 AN: 128194 AF XY: 0.0983

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 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

African (AFR) AF: 0.111 AC: 948 AN: 8552

American (AMR) AF: 0.0661 AC: 1802 AN: 27268

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 1408 AN: 10786

East Asian (EAS) AF: 0.0656 AC: 604 AN: 9202

South Asian (SAS) AF: 0.0979 AC: 5837 AN: 59594

European-Finnish (FIN) AF: 0.136 AC: 1677 AN: 12342

Middle Eastern (MID) AF: 0.125 AC: 146 AN: 1168

European-Non Finnish (NFE) AF: 0.105 AC: 16658 AN: 158546

Other (OTH) AF: 0.0990 AC: 1388 AN: 14024

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

African (AFR) AF: 0.109 AC: 4529 AN: 41406

American (AMR) AF: 0.0882 AC: 1346 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 484 AN: 3468

East Asian (EAS) AF: 0.0643 AC: 331 AN: 5148

South Asian (SAS) AF: 0.0958 AC: 460 AN: 4800

European-Finnish (FIN) AF: 0.135 AC: 1425 AN: 10536

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7275 AN: 67956

Other (OTH) AF: 0.102 AC: 216 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
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
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.50
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41311629; hg19: chr5-161529631; COSMIC: COSV62718850; COSMIC: COSV62718850;