rs418210

Variant names:

• chr5-162153977-C-T
• rs418210
• NM_198904.4:c.*609C>T

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.*609C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 153,912 control chromosomes in the GnomAD database, including 8,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8867 hom., cov: 32)
  • Exomes 𝑓: 0.22 (59 hom.)
• Consequence: GABRG2 NM_198904.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.665
• Publications: 8 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=-0.8).
• BP6: Variant 5-162153977-C-T is Benign according to our data. Variant chr5-162153977-C-T is described in ClinVar as Benign. ClinVar VariationId is 352655.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 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.*609C>T		3_prime_UTR	Exon 10 of 10	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.*609C>T		3_prime_UTR	Exon 11 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.*609C>T		3_prime_UTR	Exon 10 of 10	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.*609C>T		3_prime_UTR	Exon 10 of 10	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000414552.6	TSL:1	c.*609C>T		3_prime_UTR	Exon 11 of 11	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639111.2	TSL:1	c.*609C>T		3_prime_UTR	Exon 9 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48867 AN: 151788 Hom.: 8838 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.216 AC: 433 AN: 2006 Hom.: 59 Cov.: 0 AF XY: 0.217 AC XY: 227 AN XY: 1048

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.209 AC: 62 AN: 296

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 2 AN: 6

East Asian (EAS) AF: 0.375 AC: 6 AN: 16

South Asian (SAS) AF: 0.228 AC: 26 AN: 114

European-Finnish (FIN) AF: 0.264 AC: 112 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.195 AC: 212 AN: 1086

Other (OTH) AF: 0.217 AC: 13 AN: 60

GnomAD4 genome AF: 0.322 AC: 48941 AN: 151906 Hom.: 8867 Cov.: 32 AF XY: 0.324 AC XY: 24014 AN XY: 74228

African (AFR) AF: 0.486 AC: 20111 AN: 41422

American (AMR) AF: 0.236 AC: 3594 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 866 AN: 3472

East Asian (EAS) AF: 0.485 AC: 2502 AN: 5158

South Asian (SAS) AF: 0.291 AC: 1401 AN: 4818

European-Finnish (FIN) AF: 0.275 AC: 2902 AN: 10542

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16609 AN: 67944

Other (OTH) AF: 0.284 AC: 600 AN: 2112

Alfa AF: 0.274 Hom.: 1549

Bravo AF: 0.323

Asia WGS AF: 0.350 AC: 1211 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.26
DANN	Benign	0.56
PhyloP100		-0.67
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs418210;

hg19: chr5-161580983;

COSMIC: COSV62718144;

COSMIC: COSV62718144;