6-29588032-C-T

Variant names:

• chr6-29588032-C-T
• rs3129034
• NM_007160.4:c.88C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007160.4(OR2H2):​c.88C>T​(p.Leu30Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,006,340 control chromosomes in the GnomAD database, including 248,032 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (40381 hom., cov: 30)
  • Exomes 𝑓: 0.69 (207651 hom.)
• Consequence: OR2H2 NM_007160.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 24 publications found

Genes affected

OR2H2 (HGNC:8253): (olfactory receptor family 2 subfamily H member 2) Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms. [provided by RefSeq, Jul 2008]

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]

GABBR1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with language delay and variable cognitive abnormalities

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.811117E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2H2	NM_007160.4	c.88C>T	p.Leu30Phe	missense_variant	Exon 2 of 2	ENST00000641840.1	NP_009091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2H2	ENST00000641840.1	c.88C>T	p.Leu30Phe	missense_variant	Exon 2 of 2		NM_007160.4	ENSP00000492959.1
OR2H2	ENST00000383640.4	c.88C>T	p.Leu30Phe	missense_variant	Exon 1 of 1	6		ENSP00000373136.2
GABBR1	ENST00000355973.7	c.*2+15509G>A		intron_variant	Intron 18 of 18	2		ENSP00000348248.3

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109307 AN: 151852 Hom.: 40326 Cov.: 30

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.726

GnomAD2 exomes AF: 0.696 AC: 172101 AN: 247110 AF XY: 0.691

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.893

Gnomad FIN exome AF: 0.671

Gnomad NFE exome AF: 0.628

Gnomad OTH exome AF: 0.677

GnomAD4 exome AF: 0.693 AC: 592236 AN: 854370 Hom.: 207651 Cov.: 13 AF XY: 0.691 AC XY: 310480 AN XY: 449476

African (AFR) AF: 0.896 AC: 20881 AN: 23308

American (AMR) AF: 0.737 AC: 32457 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 13223 AN: 22290

East Asian (EAS) AF: 0.904 AC: 33687 AN: 37254

South Asian (SAS) AF: 0.748 AC: 55832 AN: 74632

European-Finnish (FIN) AF: 0.669 AC: 34897 AN: 52184

Middle Eastern (MID) AF: 0.725 AC: 3358 AN: 4632

European-Non Finnish (NFE) AF: 0.666 AC: 369839 AN: 555396

Other (OTH) AF: 0.690 AC: 28062 AN: 40658

GnomAD4 genome AF: 0.720 AC: 109421 AN: 151970 Hom.: 40381 Cov.: 30 AF XY: 0.724 AC XY: 53748 AN XY: 74264

African (AFR) AF: 0.881 AC: 36530 AN: 41454

American (AMR) AF: 0.703 AC: 10735 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1980 AN: 3470

East Asian (EAS) AF: 0.891 AC: 4579 AN: 5140

South Asian (SAS) AF: 0.786 AC: 3785 AN: 4818

European-Finnish (FIN) AF: 0.675 AC: 7124 AN: 10558

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42471 AN: 67944

Other (OTH) AF: 0.731 AC: 1536 AN: 2102

Alfa AF: 0.692 Hom.: 31831

Bravo AF: 0.731

TwinsUK AF: 0.629 AC: 2333

ALSPAC AF: 0.631 AC: 2432

ESP6500AA AF: 0.873 AC: 2637

ESP6500EA AF: 0.615 AC: 3331

ExAC AF: 0.699 AC: 82604

Asia WGS AF: 0.848 AC: 2948 AN: 3478

EpiCase AF: 0.634

EpiControl AF: 0.635

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.8
DANN	Benign	0.93
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0037	N
MetaRNN	Benign	9.8e-7	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;L
PhyloP100		-1.2
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.6	.;D
REVEL	Benign	0.035
Sift	Benign	0.15	.;T
Sift4G	Benign	0.12	.;T
Polyphen		0.0030	B;B
Vest4		0.016
MPC		0.20
ClinPred		0.010	T
GERP RS		0.68
Varity_R		0.051
gMVP		0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3129034; hg19: chr6-29555809; COSMIC: COSV63542338;