rs1233387

Positions:

• chr6-29588087-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007160.4(OR2H2):​c.143C>T​(p.Ala48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 949,472 control chromosomes in the GnomAD database, including 41,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (5631 hom., cov: 31)
  • Exomes 𝑓: 0.29 (35952 hom.)
• Consequence: OR2H2 NM_007160.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.787

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8432736E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR2H2	NM_007160.4	c.143C>T	p.Ala48Val	missense_variant	2/2	ENST00000641840.1	NP_009091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR2H2	ENST00000641840.1	c.143C>T	p.Ala48Val	missense_variant	2/2		NM_007160.4	ENSP00000492959.1
OR2H2	ENST00000383640.4	c.143C>T	p.Ala48Val	missense_variant	1/1	6		ENSP00000373136.2
GABBR1	ENST00000355973.7	c.*2+15454G>A		intron_variant		2		ENSP00000348248.3

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40603 AN: 151766 Hom.: 5623 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.292

GnomAD3 exomes AF: 0.302 AC: 74755 AN: 247266 Hom.: 12262 AF XY: 0.301 AC XY: 40469 AN XY: 134640

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.402

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.451

Gnomad SAS exome AF: 0.345

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.290 AC: 231667 AN: 797588 Hom.: 35952 Cov.: 12 AF XY: 0.292 AC XY: 123599 AN XY: 422850

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.354

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.267 AC: 40628 AN: 151884 Hom.: 5631 Cov.: 31 AF XY: 0.270 AC XY: 20072 AN XY: 74230

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.289

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.292

Alfa AF: 0.261 Hom.: 2662

Bravo AF: 0.280

TwinsUK AF: 0.237 AC: 880

ALSPAC AF: 0.242 AC: 932

ESP6500AA AF: 0.260 AC: 786

ESP6500EA AF: 0.253 AC: 1371

ExAC AF: 0.300 AC: 35604

Asia WGS AF: 0.356 AC: 1236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.81
DEOGEN2	Benign	0.0018	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0046	N
MetaRNN	Benign	0.00018	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.78	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.21	.;N
REVEL	Benign	0.045
Sift	Benign	0.50	.;T
Sift4G	Benign	0.50	.;T
Polyphen		0.0	B;B
Vest4		0.025
MPC		0.18
ClinPred		0.0021	T
GERP RS		2.0
Varity_R		0.031
gMVP		0.053

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: rs1233387; hg19: chr6-29555864; COSMIC: COSV63541930;