12-55130075-G-A

Position:

• chr12-55130075-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005243.2(OR9K2):​c.241G>A​(p.Glu81Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OR9K2 NM_001005243.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.153

Genes affected

OR9K2 (HGNC:15339): (olfactory receptor family 9 subfamily K 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11812574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR9K2	NM_001005243.2	c.241G>A	p.Glu81Lys	missense_variant	3/3	ENST00000641329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR9K2	ENST00000641329.1	c.241G>A	p.Glu81Lys	missense_variant	3/3		NM_001005243.2	P1
OR9K2	ENST00000641374.1	c.241G>A	p.Glu81Lys	missense_variant	1/1			P1
OR9K2	ENST00000641353.1	n.196-2351G>A		intron_variant, non_coding_transcript_variant
OR9K2	ENST00000641982.1	n.183+178G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460340 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726538

Gnomad4 AFR exome AF: 0.0000299

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

Bravo AF: 0.00000378

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

Feb 15, 2023

The c.307G>A (p.E103K) alteration is located in exon 1 (coding exon 1) of the OR9K2 gene. This alteration results from a G to A substitution at nucleotide position 307, causing the glutamic acid (E) at amino acid position 103 to be replaced by a lysine (K). 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	0.40
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0025	.;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.082	N
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.20	.;.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.010	.;.;N
REVEL	Benign	0.15
Sift	Uncertain	0.0010	.;.;D
Sift4G	Uncertain	0.0070	.;.;D
Polyphen		0.0	.;.;B
Vest4		0.12
MutPred		0.63		.;.;Gain of catalytic residue at A106 (P = 0.0021);
MVP		0.26
MPC		0.0086
ClinPred		0.38	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.32

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: rs1953459304; hg19: chr12-55523859; COSMIC: COSV105182324;