rs211014

Variant names:

• chr5-162149412-C-A
• rs211014
• NM_198904.4:c.1128+99C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198904.4(GABRG2):​c.1128+99C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,138,958 control chromosomes in the GnomAD database, including 42,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (7270 hom., cov: 32)
  • Exomes 𝑓: 0.26 (35289 hom.)
• Consequence: GABRG2 NM_198904.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.943
• Publications: 31 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-162149412-C-A is Benign according to our data. Variant chr5-162149412-C-A is described in ClinVar as Benign. ClinVar VariationId is 674989.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198904.4. 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.1128+99C>A		intron	N/A	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.1248+99C>A		intron	N/A	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.1248+99C>A		intron	N/A	NP_001362272.1	A0A1X7SBZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.1128+99C>A		intron	N/A	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000414552.6	TSL:1	c.1248+99C>A		intron	N/A	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639111.2	TSL:1	c.1128+99C>A		intron	N/A	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45432 AN: 151848 Hom.: 7265 Cov.: 32

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.258 AC: 254810 AN: 986992 Hom.: 35289 Cov.: 13 AF XY: 0.259 AC XY: 131415 AN XY: 506946

African (AFR) AF: 0.395 AC: 9469 AN: 23968

American (AMR) AF: 0.217 AC: 7878 AN: 36348

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 5696 AN: 22916

East Asian (EAS) AF: 0.494 AC: 17510 AN: 35420

South Asian (SAS) AF: 0.295 AC: 21493 AN: 72796

European-Finnish (FIN) AF: 0.277 AC: 11613 AN: 41954

Middle Eastern (MID) AF: 0.229 AC: 1124 AN: 4900

European-Non Finnish (NFE) AF: 0.239 AC: 168284 AN: 704142

Other (OTH) AF: 0.264 AC: 11743 AN: 44548

GnomAD4 genome AF: 0.299 AC: 45466 AN: 151966 Hom.: 7270 Cov.: 32 AF XY: 0.301 AC XY: 22378 AN XY: 74288

African (AFR) AF: 0.397 AC: 16441 AN: 41422

American (AMR) AF: 0.228 AC: 3484 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 816 AN: 3466

East Asian (EAS) AF: 0.485 AC: 2500 AN: 5150

South Asian (SAS) AF: 0.291 AC: 1402 AN: 4820

European-Finnish (FIN) AF: 0.281 AC: 2961 AN: 10556

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16960 AN: 67966

Other (OTH) AF: 0.261 AC: 550 AN: 2108

Alfa AF: 0.261 Hom.: 9302

Bravo AF: 0.297

Asia WGS AF: 0.337 AC: 1169 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.2
DANN	Benign	0.64
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs211014; hg19: chr5-161576418;