1-248180688-T-C

Position:

• chr1-248180688-T-C

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.703T>C​(p.Cys235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,612,124 control chromosomes in the GnomAD database, including 326,238 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C235Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.62 (29369 hom., cov: 32)
  • Exomes 𝑓: 0.64 (296869 hom.)
• Consequence: OR2M2 NM_001004688.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.27

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=3.7955297E-6).
• BP6: Variant 1-248180688-T-C is Benign according to our data. Variant chr1-248180688-T-C is described in ClinVar as [Benign]. Clinvar id is 767775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR2M2	NM_001004688.2	c.703T>C	p.Cys235Arg	missense_variant	2/2	ENST00000641836.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR2M2	ENST00000641836.1	c.703T>C	p.Cys235Arg	missense_variant	2/2		NM_001004688.2	P1
OR2M2	ENST00000641211.1	c.703T>C	p.Cys235Arg	missense_variant	3/3			P1

Frequencies

GnomAD3 genomes AF: 0.619 AC: 94122 AN: 151942 Hom.: 29337 Cov.: 32

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.614 AC: 149832 AN: 244222 Hom.: 47209 AF XY: 0.619 AC XY: 81637 AN XY: 131968

Gnomad AFR exome AF: 0.601

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.555

Gnomad EAS exome AF: 0.432

Gnomad SAS exome AF: 0.598

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.633

GnomAD4 exome AF: 0.636 AC: 928405 AN: 1460064 Hom.: 296869 Cov.: 85 AF XY: 0.635 AC XY: 461505 AN XY: 726396

Gnomad4 AFR exome AF: 0.603

Gnomad4 AMR exome AF: 0.599

Gnomad4 ASJ exome AF: 0.557

Gnomad4 EAS exome AF: 0.438

Gnomad4 SAS exome AF: 0.606

Gnomad4 FIN exome AF: 0.637

Gnomad4 NFE exome AF: 0.650

Gnomad4 OTH exome AF: 0.632

GnomAD4 genome AF: 0.619 AC: 94197 AN: 152060 Hom.: 29369 Cov.: 32 AF XY: 0.618 AC XY: 45904 AN XY: 74312

Gnomad4 AFR AF: 0.596

Gnomad4 AMR AF: 0.620

Gnomad4 ASJ AF: 0.557

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.606

Gnomad4 FIN AF: 0.629

Gnomad4 NFE AF: 0.650

Gnomad4 OTH AF: 0.636

Alfa AF: 0.634 Hom.: 13166

Bravo AF: 0.617

ESP6500AA AF: 0.571 AC: 2517

ESP6500EA AF: 0.627 AC: 5393

ExAC AF: 0.611 AC: 74202

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	Oct 13, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.17
DEOGEN2	Benign	0.0045	T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00052	N
LIST_S2	Benign	0.0062	.;.;T
MetaRNN	Benign	0.0000038	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N;N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.17	T
PROVEAN	Benign	5.1	.;.;N
REVEL	Benign	0.020
Sift	Benign	0.52	.;.;T
Sift4G	Benign	0.50	.;.;T
Polyphen		0.0	B;B;B
Vest4		0.0090
MPC		0.19
ClinPred		0.0042	T
GERP RS		1.1
Varity_R		0.074
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4916104; hg19: chr1-248343990; COSMIC: COSV62897713;