6-29588489-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007160.4(OR2H2):c.545T>C(p.Leu182Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR2H2 NM_007160.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR2H2	NM_007160.4	c.545T>C	p.Leu182Pro	missense_variant	2/2	ENST00000641840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR2H2	ENST00000641840.1	c.545T>C	p.Leu182Pro	missense_variant	2/2		NM_007160.4	P1
OR2H2	ENST00000383640.4	c.545T>C	p.Leu182Pro	missense_variant	1/1			P1
GABBR1	ENST00000355973.7	c.*2+15052A>G		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 913342 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 477308

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 20, 2022

The c.545T>C (p.L182P) alteration is located in exon 1 (coding exon 1) of the OR2H2 gene. This alteration results from a T to C substitution at nucleotide position 545, causing the leucine (L) at amino acid position 182 to be replaced by a proline (P). 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.0036	T
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.34	T
Polyphen		1.0	D;D
Vest4		0.76
MutPred		0.57		Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);
MVP		0.46
MPC		0.95
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.86
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-29556266;