chr1-248295304-C-T

Variant names:

• chr1-248295304-C-T
• rs779943961
• NM_001004692.2:c.275G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004692.2(OR2T12):​c.275G>A​(p.Arg92His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00004 in 150,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0000062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR2T12 NM_001004692.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.895
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05141911).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004692.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR2T12	NM_001004692.2	MANE Select	c.275G>A	p.Arg92His	missense	Exon 3 of 3	NP_001004692.1	Q8NG77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR2T12	ENST00000641276.1	MANE Select	c.275G>A	p.Arg92His	missense	Exon 3 of 3	ENSP00000493000.1	Q8NG77

Frequencies

GnomAD3 genomes AF: 0.0000400 AC: 6 AN: 150110 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000959

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 246498 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000617 AC: 9 AN: 1458690 Hom.: 0 Cov.: 51 AF XY: 0.00000827 AC XY: 6 AN XY: 725606

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.0000224 AC: 1 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4462

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110586

Other (OTH) AF: 0.00 AC: 0 AN: 60190

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000506268), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000400 AC: 6 AN: 150110 Hom.: 0 Cov.: 24 AF XY: 0.0000137 AC XY: 1 AN XY: 73144

African (AFR) AF: 0.00 AC: 0 AN: 40640

American (AMR) AF: 0.0000666 AC: 1 AN: 15020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4598

European-Finnish (FIN) AF: 0.0000959 AC: 1 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000592 AC: 4 AN: 67606

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.32
DANN	Benign	0.91
DEOGEN2	Benign	0.00060	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.00093	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.90
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.054
Sift	Benign	0.29	T
Sift4G	Benign	0.077	T
Polyphen		0.32	B
Vest4		0.060
MVP		0.085
MPC		0.67
ClinPred		0.059	T
GERP RS		-3.1
Varity_R		0.043
gMVP		0.082
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs779943961; hg19: chr1-248458606; COSMIC: COSV58777309;