5-162102565-A-G

Variant names:

• chr5-162102565-A-G
• rs211035
• ENST00000414552.6:c.643A>G

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.643A>G​(p.Ile215Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 454,032 control chromosomes in the GnomAD database, including 151,858 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I215L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.82 (51485 hom., cov: 31)
  • Exomes 𝑓: 0.81 (100373 hom.)
• Consequence: GABRG2 NM_198903.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.00
• Publications: 20 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=1.5540011E-6).
• BP6: Variant 5-162102565-A-G is Benign according to our data. Variant chr5-162102565-A-G is described in ClinVar as Benign. ClinVar VariationId is 585903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.847 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.631+1248A>G		intron	N/A	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.643A>G	p.Ile215Val	missense	Exon 6 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.643A>G	p.Ile215Val	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.643A>G	p.Ile215Val	missense	Exon 6 of 11	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.631+1248A>G		intron	N/A	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000639111.2	TSL:1	c.631+1248A>G		intron	N/A	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124892 AN: 151948 Hom.: 51453 Cov.: 31

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.848

Gnomad MID AF: 0.792

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.820

GnomAD2 exomes AF: 0.823 AC: 105667 AN: 128346 AF XY: 0.820

Gnomad AFR exome AF: 0.852

Gnomad AMR exome AF: 0.894

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.755

Gnomad FIN exome AF: 0.840

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.799

GnomAD4 exome AF: 0.814 AC: 245848 AN: 301962 Hom.: 100373 Cov.: 0 AF XY: 0.814 AC XY: 140140 AN XY: 172066

African (AFR) AF: 0.848 AC: 7264 AN: 8562

American (AMR) AF: 0.892 AC: 24319 AN: 27276

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 8293 AN: 10786

East Asian (EAS) AF: 0.749 AC: 6897 AN: 9204

South Asian (SAS) AF: 0.840 AC: 50089 AN: 59640

European-Finnish (FIN) AF: 0.834 AC: 10311 AN: 12356

Middle Eastern (MID) AF: 0.769 AC: 931 AN: 1210

European-Non Finnish (NFE) AF: 0.796 AC: 126465 AN: 158870

Other (OTH) AF: 0.802 AC: 11279 AN: 14058

GnomAD4 genome AF: 0.822 AC: 124981 AN: 152070 Hom.: 51485 Cov.: 31 AF XY: 0.824 AC XY: 61274 AN XY: 74324

African (AFR) AF: 0.855 AC: 35445 AN: 41478

American (AMR) AF: 0.855 AC: 13048 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2671 AN: 3472

East Asian (EAS) AF: 0.746 AC: 3848 AN: 5160

South Asian (SAS) AF: 0.850 AC: 4093 AN: 4816

European-Finnish (FIN) AF: 0.848 AC: 8965 AN: 10578

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54277 AN: 67994

Other (OTH) AF: 0.821 AC: 1725 AN: 2102

Alfa AF: 0.781 Hom.: 5455

Bravo AF: 0.824

TwinsUK AF: 0.801 AC: 2970

ALSPAC AF: 0.806 AC: 3105

ExAC AF: 0.793 AC: 10420

Asia WGS AF: 0.811 AC: 2824 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 74 (1)
-	-	1	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.13
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.000030	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.029
Sift	Benign	0.99	T
Sift4G	Benign	0.13	T
Vest4		0.024
MPC		1.1
ClinPred		0.00014	T
GERP RS		0.23
gMVP		0.20
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: rs211035; hg19: chr5-161529571; COSMIC: COSV62715958; COSMIC: COSV62715958;