1-248180689-G-A

Position:

• chr1-248180689-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001004688.2(OR2M2):​c.704G>A​(p.Cys235Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,612,508 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C235R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (85 hom.)
• Consequence: OR2M2 NM_001004688.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.76

Genes affected

OR2M2 (HGNC:8268): (olfactory receptor family 2 subfamily M 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036321282).
• BP6: Variant 1-248180689-G-A is Benign according to our data. Variant chr1-248180689-G-A is described in ClinVar as [Benign]. Clinvar id is 783322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR2M2	NM_001004688.2	c.704G>A	p.Cys235Tyr	missense_variant	2/2	ENST00000641836.1	NP_001004688.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR2M2	ENST00000641836.1	c.704G>A	p.Cys235Tyr	missense_variant	2/2		NM_001004688.2	ENSP00000493201	P1
OR2M2	ENST00000641211.1	c.704G>A	p.Cys235Tyr	missense_variant	3/3			ENSP00000492974	P1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2914 AN: 152092 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00488 AC: 1225 AN: 250960 Hom.: 30 AF XY: 0.00375 AC XY: 509 AN XY: 135628

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00209 AC: 3052 AN: 1460298 Hom.: 85 Cov.: 33 AF XY: 0.00179 AC XY: 1300 AN XY: 726504

Gnomad4 AFR exome AF: 0.0707

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000534

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.00453

GnomAD4 genome AF: 0.0191 AC: 2911 AN: 152210 Hom.: 94 Cov.: 32 AF XY: 0.0181 AC XY: 1349 AN XY: 74412

Gnomad4 AFR AF: 0.0666

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00927 Hom.: 25

Bravo AF: 0.0222

ESP6500AA AF: 0.0313 AC: 138

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00622 AC: 755

EpiCase AF: 0.000218

EpiControl AF: 0.000356

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 03, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.26
DANN	Benign	0.43
DEOGEN2	Benign	0.0038	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.12	.;.;T
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.47	N;N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	1.9	.;.;N
REVEL	Benign	0.050
Sift	Uncertain	0.013	.;.;D
Sift4G	Uncertain	0.0020	.;.;D
Polyphen		0.0	B;B;B
Vest4		0.041
MVP		0.030
MPC		0.18
ClinPred		0.0048	T
GERP RS		0.80
Varity_R		0.077
gMVP		0.10

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: rs142589543; hg19: chr1-248343991; COSMIC: COSV62898580;