rs375083192

chr5-161326369-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Moderate BP6_Moderate BS1 BS2

The NM_001371727.1(GABRB2):c.1190C>T(p.Thr397Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict 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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. T397T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: GABRB2 NM_001371727.1 missense, splice_region
• Scores: Splicing: ADA: 0.001893
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.94

Genes affected

GABRB2 (HGNC:4082): (gamma-aminobutyric acid type A receptor subunit beta2) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 2 subunit. It is mapped to chromosome 5q34 in a cluster comprised of genes encoding alpha 1 and gamma 2 subunits of the GABA A receptor. Alternative splicing of this gene generates 2 transcript variants, differing by a 114 bp insertion. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GABRB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.1578053).
• BP6: Variant 5-161326369-G-A is Benign according to our data. Variant chr5-161326369-G-A is described in ClinVar as [Benign]. Clinvar id is 533531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000904 (132/1460970) while in subpopulation NFE AF= 0.000114 (127/1111458). AF 95% confidence interval is 0.0000976. There are 0 homozygotes in gnomad4_exome. There are 61 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB2	NM_001371727.1	c.1190C>T	p.Thr397Met	missense_variant, splice_region_variant	9/10	ENST00000393959.6
GABRB2	NM_021911.3	c.1190C>T	p.Thr397Met	missense_variant, splice_region_variant	10/11
GABRB2	NM_000813.3	c.1077+4514C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB2	ENST00000393959.6	c.1190C>T	p.Thr397Met	missense_variant, splice_region_variant	9/10	1	NM_001371727.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000684 AC: 17 AN: 248474 Hom.: 0 AF XY: 0.0000520 AC XY: 7 AN XY: 134548

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000904 AC: 132 AN: 1460970 Hom.: 0 Cov.: 30 AF XY: 0.0000839 AC XY: 61 AN XY: 726816

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74468

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.52	D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.12
Sift	Benign	0.10	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.084	B;B
Vest4		0.45
MVP		0.59
MPC		0.53
ClinPred		0.047	T
GERP RS		4.5
Varity_R		0.037
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.082
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: rs375083192; hg19: chr5-160753376; COSMIC: COSV50905351; COSMIC: COSV50905351;