4-47425856-C-G

Position:

• chr4-47425856-C-G

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.

• 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	Protein	UniProt
GABRB1	NM_000812.4	c.1263C>G	p.His421Gln	missense_variant	9/9	ENST00000295454.8	NP_000803.2
GABRB1	XM_024453976.2	c.1164C>G	p.His388Gln	missense_variant	9/9		XP_024309744.1
GABRB1	XM_024453977.2	c.1164C>G	p.His388Gln	missense_variant	10/10		XP_024309745.1
GABRB1	XM_017007985.2	c.612C>G	p.His204Gln	missense_variant	5/5		XP_016863474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRB1	ENST00000295454.8	c.1263C>G	p.His421Gln	missense_variant	9/9	1	NM_000812.4	ENSP00000295454.3

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
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	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
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;