rs121909672

chr5-162149168-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_198904.4(GABRG2):c.983A>T(p.Lys328Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K328N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.20

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_198904.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-162149169-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1706879.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, GABRG2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 5-162149168-A-T is Pathogenic according to our data. Variant chr5-162149168-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 16207.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-162149168-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG2	NM_198904.4	c.983A>T	p.Lys328Met	missense_variant	8/10	ENST00000639213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG2	ENST00000639213.2	c.983A>T	p.Lys328Met	missense_variant	8/10	1	NM_198904.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Febrile seizures, familial, 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.79	T
Polyphen		1.0, 1.0	.;.;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.89
MutPred		0.85		.;.;.;.;Loss of ubiquitination at K328 (P = 0.0224);.;Loss of ubiquitination at K328 (P = 0.0224);.;Loss of ubiquitination at K328 (P = 0.0224);.;Loss of ubiquitination at K328 (P = 0.0224);.;.;Loss of ubiquitination at K328 (P = 0.0224);
MVP		0.95
MPC		3.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.83
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909672; hg19: chr5-161576174;