6-29603586-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001470.4(GABBR1):c.2843G>A(p.Arg948Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,591,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: GABBR1 NM_001470.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

GABBR1 (HGNC:4070): (gamma-aminobutyric acid type B receptor subunit 1) This gene encodes a receptor for gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. This receptor functions as a heterodimer with GABA(B) receptor 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy. Alternative splicing generates multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GABBR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.026582628).
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR1	NM_001470.4	c.2843G>A	p.Arg948Gln	missense_variant	23/23	ENST00000377034.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR1	ENST00000377034.9	c.2843G>A	p.Arg948Gln	missense_variant	23/23	1	NM_001470.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151908 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000171 AC: 37 AN: 216420 Hom.: 0 AF XY: 0.000153 AC XY: 18 AN XY: 117766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000128

Gnomad ASJ exome AF: 0.00205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000569

GnomAD4 exome AF: 0.000111 AC: 160 AN: 1439706 Hom.: 0 Cov.: 31 AF XY: 0.000115 AC XY: 82 AN XY: 714468

Gnomad4 AFR exome AF: 0.0000609

Gnomad4 AMR exome AF: 0.000166

Gnomad4 ASJ exome AF: 0.00137

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0000364

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000771

Gnomad4 OTH exome AF: 0.000303

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 151908 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74204

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000369 AC: 2

ExAC AF: 0.000162 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.2843G>A (p.R948Q) alteration is located in exon 23 (coding exon 22) of the GABBR1 gene. This alteration results from a G to A substitution at nucleotide position 2843, causing the arginine (R) at amino acid position 948 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.033
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.66	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.12	T;T;T;D
Sift4G	Benign	0.077	T;T;T;T
Polyphen		0.79, 0.80	.;P;.;P
Vest4		0.23
MVP		0.76
MPC		1.0
ClinPred		0.013	T
GERP RS		3.6
Varity_R		0.18
gMVP		0.29

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: rs145168605; hg19: chr6-29571363; COSMIC: COSV63541789; COSMIC: COSV63541789;