rs41311286

Positions:

• chr4-47425856-C-G
• chr4-47425856-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000812.4(GABRB1):​c.1263C>G​(p.His421Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,614,120 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. H421H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (5 hom.)
• Consequence: GABRB1 NM_000812.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0530

Genes affected

GABRB1 (HGNC:4081): (gamma-aminobutyric acid type A receptor subunit beta1) 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 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011458993).
• BP6: Variant 4-47425856-C-G is Benign according to our data. Variant chr4-47425856-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 445620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB1	NM_000812.4	c.1263C>G	p.His421Gln	missense_variant	9/9	ENST00000295454.8
GABRB1	XM_024453976.2	c.1164C>G	p.His388Gln	missense_variant	9/9
GABRB1	XM_024453977.2	c.1164C>G	p.His388Gln	missense_variant	10/10
GABRB1	XM_017007985.2	c.612C>G	p.His204Gln	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB1	ENST00000295454.8	c.1263C>G	p.His421Gln	missense_variant	9/9	1	NM_000812.4	P1

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 328 AN: 152226 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00249 AC: 623 AN: 250638 Hom.: 1 AF XY: 0.00245 AC XY: 332 AN XY: 135586

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00412

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00307 AC: 4486 AN: 1461776 Hom.: 5 Cov.: 31 AF XY: 0.00300 AC XY: 2178 AN XY: 727182

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00357

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152344 Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74498

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00367

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00304 Hom.: 0

Bravo AF: 0.00220

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00260 AC: 316

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GABRB1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 02, 2017	- -

GABRB1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 31, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.13
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.36
MutPred		0.15		Gain of solvent accessibility (P = 0.0021);
MVP		0.68
MPC		0.51
ClinPred		0.0050	T
GERP RS		0.39
Varity_R		0.060
gMVP		0.80

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: rs41311286; hg19: chr4-47427873;