5-162067984-G-GAA

Variant names:

• chr5-162067984-G-GAA
• rs771282908
• NM_198904.4:c.-5_-4dupAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_198904.4(GABRG2):​c.-5_-4dupAA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,261,312 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000050 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: GABRG2 NM_198904.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.142
• Publications: 1 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000502 (7/139390) while in subpopulation EAS AF = 0.00104 (5/4810). AF 95% confidence interval is 0.000409. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 7 AD gene.

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.-5_-4dupAA		5_prime_UTR	Exon 1 of 10	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.-5_-4dupAA		5_prime_UTR	Exon 1 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.-5_-4dupAA		5_prime_UTR	Exon 1 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.-5_-4dupAA		5_prime_UTR	Exon 1 of 10	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000414552.6	TSL:1	c.-5_-4dupAA		5_prime_UTR	Exon 1 of 11	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639111.2	TSL:1	c.-5_-4dupAA		5_prime_UTR	Exon 1 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes AF: 0.0000502 AC: 7 AN: 139390 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00104

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000476 AC: 33 AN: 69360 AF XY: 0.000428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000569

Gnomad ASJ exome AF: 0.000424

Gnomad EAS exome AF: 0.00164

Gnomad FIN exome AF: 0.000282

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000223 AC: 250 AN: 1121922 Hom.: 0 Cov.: 0 AF XY: 0.000200 AC XY: 113 AN XY: 564980

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000190 AC: 5 AN: 26332

American (AMR) AF: 0.000104 AC: 4 AN: 38406

Ashkenazi Jewish (ASJ) AF: 0.0000465 AC: 1 AN: 21506

East Asian (EAS) AF: 0.000624 AC: 20 AN: 32050

South Asian (SAS) AF: 0.000212 AC: 16 AN: 75324

European-Finnish (FIN) AF: 0.000118 AC: 5 AN: 42298

Middle Eastern (MID) AF: 0.000212 AC: 1 AN: 4706

European-Non Finnish (NFE) AF: 0.000228 AC: 190 AN: 834308

Other (OTH) AF: 0.000170 AC: 8 AN: 46992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000502 AC: 7 AN: 139390 Hom.: 0 Cov.: 31 AF XY: 0.0000593 AC XY: 4 AN XY: 67466

African (AFR) AF: 0.00 AC: 0 AN: 38086

American (AMR) AF: 0.000144 AC: 2 AN: 13902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3296

East Asian (EAS) AF: 0.00104 AC: 5 AN: 4810

South Asian (SAS) AF: 0.00 AC: 0 AN: 4356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63578

Other (OTH) AF: 0.00 AC: 0 AN: 1918

Alfa AF: 0.000399 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771282908; hg19: chr5-161494990; COSMIC: COSV62723030; COSMIC: COSV62723030;