chr9-122553777-A-G

Position:

• chr9-122553777-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004457.2(OR1N2):​c.566A>G​(p.Lys189Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,613,946 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: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: OR1N2 NM_001004457.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0330

Genes affected

OR1N2 (HGNC:15111): (olfactory receptor family 1 subfamily N 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]

OR1L8 (HGNC:15110): (olfactory receptor family 1 subfamily L member 8) 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]

ENSG00000234156 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014955401).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR1N2	NM_001004457.2	c.566A>G	p.Lys189Arg	missense_variant	1/1	ENST00000373688.3	NP_001004457.2
OR1L8	XM_017014285.2	c.*23-7248T>C		intron_variant			XP_016869774.1
OR1J2	XR_007061271.1	n.1541-26176A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR1N2	ENST00000373688.3	c.566A>G	p.Lys189Arg	missense_variant	1/1	6	NM_001004457.2	ENSP00000362792.3
ENSG00000234156	ENST00000431442.2	n.1362+50907A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 250990 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1461844 Hom.: 0 Cov.: 46 AF XY: 0.000171 AC XY: 124 AN XY: 727218

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000436

EpiControl AF: 0.00

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

Sep 14, 2021

The c.608A>G (p.K203R) alteration is located in exon 1 (coding exon 1) of the OR1N2 gene. This alteration results from a A to G substitution at nucleotide position 608, causing the lysine (K) at amino acid position 203 to be replaced by an arginine (R). 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	0.079
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0051	.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.38	T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.74	.;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.030	N;.
REVEL	Benign	0.067
Sift	Benign	0.16	T;.
Polyphen		0.61	.;P
MVP		0.39
MPC		0.51
ClinPred		0.049	T
GERP RS		1.9
Varity_R		0.081
gMVP		0.085

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: rs138880886; hg19: chr9-125316056;