rs4478844

Positions:

• chr1-247965938-G-A
• chr1-247965938-G-C

Variant summary

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

The NM_001004491.2(OR2AK2):​c.562G>A​(p.Val188Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 1,608,454 control chromosomes in the GnomAD database, including 304,847 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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 0.50 (21840 hom., cov: 32)
  • Exomes 𝑓: 0.62 (283007 hom.)
• Consequence: OR2AK2 NM_001004491.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.930

Genes affected

OR2AK2 (HGNC:19569): (olfactory receptor family 2 subfamily AK 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]

OR2L13 (HGNC:19578): (olfactory receptor family 2 subfamily L member 13) 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.161648E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR2AK2	NM_001004491.2	c.562G>A	p.Val188Met	missense_variant	1/1	ENST00000366480.5	NP_001004491.2
OR2L13	NM_001304535.3	c.-19+28554G>A		intron_variant			NP_001291464.1
OR2L13	NM_175911.5	c.-144+28554G>A		intron_variant			NP_787107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR2AK2	ENST00000366480.5	c.562G>A	p.Val188Met	missense_variant	1/1	6	NM_001004491.2	ENSP00000355436.4

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75683 AN: 151808 Hom.: 21844 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.640

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.544

GnomAD3 exomes AF: 0.573 AC: 141548 AN: 247002 Hom.: 42327 AF XY: 0.579 AC XY: 77126 AN XY: 133292

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.594

Gnomad ASJ exome AF: 0.627

Gnomad EAS exome AF: 0.458

Gnomad SAS exome AF: 0.521

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.612

GnomAD4 exome AF: 0.617 AC: 898631 AN: 1456528 Hom.: 283007 Cov.: 43 AF XY: 0.615 AC XY: 445470 AN XY: 724120

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.590

Gnomad4 ASJ exome AF: 0.618

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.524

Gnomad4 FIN exome AF: 0.650

Gnomad4 NFE exome AF: 0.646

Gnomad4 OTH exome AF: 0.601

GnomAD4 genome AF: 0.498 AC: 75674 AN: 151926 Hom.: 21840 Cov.: 32 AF XY: 0.498 AC XY: 36970 AN XY: 74244

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.631

Gnomad4 EAS AF: 0.449

Gnomad4 SAS AF: 0.525

Gnomad4 FIN AF: 0.648

Gnomad4 NFE AF: 0.637

Gnomad4 OTH AF: 0.543

Alfa AF: 0.610 Hom.: 74282

Bravo AF: 0.480

TwinsUK AF: 0.648 AC: 2403

ALSPAC AF: 0.655 AC: 2524

ESP6500AA AF: 0.194 AC: 856

ESP6500EA AF: 0.641 AC: 5510

ExAC AF: 0.563 AC: 68336

Asia WGS AF: 0.465 AC: 1622 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0013	.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0000082	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Benign	0.22	T
REVEL	Benign	0.045
Polyphen		1.0	.;D
MPC		0.24
ClinPred		0.045	T
GERP RS		0.63
Varity_R		0.29
gMVP		0.10

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: rs4478844; hg19: chr1-248129240; COSMIC: COSV63548286;