1-248294821-C-G

Variant names:

• chr1-248294821-C-G
• rs140090926
• NM_001004692.2:c.758G>C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001004692.2(OR2T12):​c.758G>C​(p.Gly253Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,010 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: OR2T12 NM_001004692.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.00

Genes affected

OR2T12 (HGNC:19592): (olfactory receptor family 2 subfamily T member 12) 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011195511).
• BP6: Variant 1-248294821-C-G is Benign according to our data. Variant chr1-248294821-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2280874.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2T12	NM_001004692.2	c.758G>C	p.Gly253Ala	missense_variant	Exon 3 of 3	ENST00000641276.1	NP_001004692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2T12	ENST00000641276.1	c.758G>C	p.Gly253Ala	missense_variant	Exon 3 of 3		NM_001004692.2	ENSP00000493000.1

Frequencies

GnomAD3 genomes AF: 0.000968 AC: 147 AN: 151868 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000823

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000844 AC: 212 AN: 251142 Hom.: 1 AF XY: 0.000847 AC XY: 115 AN XY: 135726

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00112 AC: 1639 AN: 1461036 Hom.: 4 Cov.: 101 AF XY: 0.00109 AC XY: 789 AN XY: 726876

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.000974 AC: 148 AN: 151974 Hom.: 0 Cov.: 29 AF XY: 0.000889 AC XY: 66 AN XY: 74266

Gnomad4 AFR AF: 0.000845

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000574 Hom.: 0

Bravo AF: 0.00110

ExAC AF: 0.000898 AC: 109

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 30, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.14
DANN	Benign	0.061
DEOGEN2	Benign	0.00032	T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.17	.;T
M_CAP	Benign	0.00063	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.3	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	3.2	.;N
REVEL	Benign	0.052
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	.;T
Polyphen		0.0	B;B
Vest4		0.050
MVP		0.11
MPC		0.48
ClinPred		0.011	T
GERP RS		0.23
Varity_R		0.031
gMVP		0.065

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140090926; hg19: chr1-248458123; COSMIC: COSV58776884;