5-162067984-GAAAA-GA

Variant names:

• chr5-162067984-GAAA-G
• rs771282908
• NM_198904.4:c.-6_-4delAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_198904.4(GABRG2):​c.-6_-4delAAA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,124,176 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GABRG2 NM_198904.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.819
• 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: Uncertain_significance. The variant received 0 ACMG points.

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000865 AC: 6 AN: 69360 AF XY: 0.0000802

Gnomad AFR exome AF: 0.000205

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000424

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000917

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.0000213 AC: 24 AN: 1124176 Hom.: 0 AF XY: 0.0000177 AC XY: 10 AN XY: 566120

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

African (AFR) AF: 0.0000379 AC: 1 AN: 26372

American (AMR) AF: 0.00 AC: 0 AN: 38424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21526

East Asian (EAS) AF: 0.00 AC: 0 AN: 32082

South Asian (SAS) AF: 0.0000265 AC: 2 AN: 75394

European-Finnish (FIN) AF: 0.0000473 AC: 2 AN: 42284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4710

European-Non Finnish (NFE) AF: 0.0000203 AC: 17 AN: 836312

Other (OTH) AF: 0.0000425 AC: 2 AN: 47072

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.82

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: rs771282908; hg19: chr5-161494990;