rs1233387

Variant names:

• chr6-29588087-C-T
• rs1233387
• NM_007160.4:c.143C>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.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. 15/21 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 0.27 (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
• Publications: 23 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=1.8432736E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007160.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR2H2	NM_007160.4	MANE Select	c.143C>T	p.Ala48Val	missense	Exon 2 of 2	NP_009091.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR2H2	ENST00000641840.1	MANE Select	c.143C>T	p.Ala48Val	missense	Exon 2 of 2	ENSP00000492959.1	O95918
	OR2H2	ENST00000383640.4	TSL:6	c.143C>T	p.Ala48Val	missense	Exon 1 of 1	ENSP00000373136.2	O95918
	GABBR1	ENST00000355973.7	TSL:2	c.*2+15454G>A		intron	N/A	ENSP00000348248.3	Q9UBS5-2

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

GnomAD2 exomes AF: 0.302 AC: 74755 AN: 247266 AF XY: 0.301

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 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

African (AFR) AF: 0.266 AC: 5709 AN: 21430

American (AMR) AF: 0.391 AC: 17191 AN: 43920

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 6607 AN: 22030

East Asian (EAS) AF: 0.503 AC: 18534 AN: 36872

South Asian (SAS) AF: 0.354 AC: 25967 AN: 73444

European-Finnish (FIN) AF: 0.198 AC: 10344 AN: 52222

Middle Eastern (MID) AF: 0.417 AC: 1879 AN: 4506

European-Non Finnish (NFE) AF: 0.266 AC: 134195 AN: 504468

Other (OTH) AF: 0.290 AC: 11241 AN: 38696

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

African (AFR) AF: 0.260 AC: 10768 AN: 41406

American (AMR) AF: 0.315 AC: 4806 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1002 AN: 3468

East Asian (EAS) AF: 0.466 AC: 2392 AN: 5130

South Asian (SAS) AF: 0.376 AC: 1806 AN: 4798

European-Finnish (FIN) AF: 0.193 AC: 2042 AN: 10558

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16866 AN: 67956

Other (OTH) AF: 0.292 AC: 614 AN: 2104

Alfa AF: 0.265 Hom.: 5068

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 v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0046	N
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.78	N
PhyloP100		-0.79
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
Vest4		0.025
MPC		0.18
ClinPred		0.0021	T
GERP RS		2.0
Varity_R		0.031
gMVP		0.053
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: rs1233387; hg19: chr6-29555864; COSMIC: COSV63541930;