6-29603604-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001470.4(GABBR1):c.2825C>T(p.Pro942Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,431,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GABBR1 NM_001470.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABBR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.1430448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR1	NM_001470.4	c.2825C>T	p.Pro942Leu	missense_variant	23/23	ENST00000377034.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR1	ENST00000377034.9	c.2825C>T	p.Pro942Leu	missense_variant	23/23	1	NM_001470.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431258 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 709946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Jan 10, 2022

The c.2825C>T (p.P942L) alteration is located in exon 23 (coding exon 22) of the GABBR1 gene. This alteration results from a C to T substitution at nucleotide position 2825, causing the proline (P) at amino acid position 942 to be replaced by a leucine (L). 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	0.069
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	21
Dann	Benign	0.63
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.93	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.069, 0.041	.;B;.;B
Vest4		0.34
MutPred		0.23		.;.;.;Loss of glycosylation at P942 (P = 0.0175);
MVP		0.70
MPC		0.88
ClinPred		0.40	T
GERP RS		3.6
Varity_R		0.095
gMVP		0.35

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: rs779359819; hg19: chr6-29571381;