1-247965423-G-A

Position:

• chr1-247965423-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001004491.2(OR2AK2):​c.47G>A​(p.Gly16Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,612,996 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (11 hom.)
• Consequence: OR2AK2 NM_001004491.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.103

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006735295).
• BP6: Variant 1-247965423-G-A is Benign according to our data. Variant chr1-247965423-G-A is described in ClinVar as [Benign]. Clinvar id is 719377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00681 (1037/152248) while in subpopulation AFR AF= 0.023 (954/41532). AF 95% confidence interval is 0.0218. There are 15 homozygotes in gnomad4. There are 508 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR2AK2	NM_001004491.2	c.47G>A	p.Gly16Asp	missense_variant	1/1	ENST00000366480.5	NP_001004491.2
OR2L13	NM_001304535.3	c.-19+28039G>A		intron_variant			NP_001291464.1
OR2L13	NM_175911.5	c.-144+28039G>A		intron_variant			NP_787107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR2AK2	ENST00000366480.5	c.47G>A	p.Gly16Asp	missense_variant	1/1	6	NM_001004491.2	ENSP00000355436.4

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1022 AN: 152130 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00188 AC: 469 AN: 249926 Hom.: 5 AF XY: 0.00148 AC XY: 200 AN XY: 135098

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.000811 AC: 1185 AN: 1460748 Hom.: 11 Cov.: 31 AF XY: 0.000764 AC XY: 555 AN XY: 726678

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00681 AC: 1037 AN: 152248 Hom.: 15 Cov.: 32 AF XY: 0.00682 AC XY: 508 AN XY: 74438

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00150 Hom.: 5

Bravo AF: 0.00783

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00222 AC: 270

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000384

EpiControl AF: 0.000239

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.038	.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	.;M
PrimateAI	Benign	0.23	T
REVEL	Benign	0.10
Polyphen		0.53	.;P
MVP		0.20
MPC		0.041
ClinPred		0.061	T
GERP RS		-3.0
Varity_R		0.21
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs74153215; hg19: chr1-248128725;