rs771660227

Positions:

• chr5-162153085-C-G
• chr5-162153085-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_198904.4(GABRG2):​c.1153-8C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003456
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.157

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13893521).
• BP6: Variant 5-162153085-C-G is Benign according to our data. Variant chr5-162153085-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 794672.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.1153-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.1153-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_198904.4	ENSP00000491909	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 74 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 12, 2021

The inherited c.1153-8C>G variant identified in the GABRG2 gene is an intronic variant at the -8 (non-canonical) position of intron 9/9 of GABRG2 (NM_198904.2). This variant is absent from gnomAD(v3.1) suggesting it is not a common benign variant in the populations represented in that database. SpliceAI does not predict this variant to alter splicing, although the Transcript inferred Pathogenicity Score (TraP) score for this variant is 0.277, which is >95% score-percentile, suggesting it is possibly damaging to splicing. This variant is reported by a single submitter in ClinVar as Likely Benign (VarID:794672), although specific criteria used for this classification was not available for our review. To our current knowledge this variant has not been reported in affected individuals in the literature, although variants within the final exon of GABRG2, which would presumably be affected by this variant were it to alter splicing, have been reported [PMID:27066572, 27367160]. Given the lack of compelling evidence for its pathogenicity, the inherited c.1153-8C>G variant identified in the GABRG2 gene is reported as a Variant of Uncertain Significance. -

Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.48
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.14	T
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		-1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.020		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: rs771660227; hg19: chr5-161580091;