chr1-248650212-C-G

Variant names:

• chr1-248650212-C-G
• rs563007702
• NM_001001824.2:c.673G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001824.2(OR2T27):​c.673G>C​(p.Val225Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000735 in 135,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V225I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000074 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000066 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR2T27 NM_001001824.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.319
• Publications: 1 publications found

Genes affected

OR2T27 (HGNC:31252): (olfactory receptor family 2 subfamily T member 27) 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14722878).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001824.2. 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
	OR2T27	NM_001001824.2	MANE Select	c.673G>C	p.Val225Leu	missense	Exon 2 of 2	NP_001001824.1	Q8NH04
	OR2T27	NM_001386060.1		c.673G>C	p.Val225Leu	missense	Exon 3 of 3	NP_001372989.1	Q8NH04

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR2T27	ENST00000460972.4	TSL:6 MANE Select	c.673G>C	p.Val225Leu	missense	Exon 2 of 2	ENSP00000493412.1	Q8NH04
	OR2T27	ENST00000641652.1		c.673G>C	p.Val225Leu	missense	Exon 3 of 3	ENSP00000493434.1	Q8NH04

Frequencies

GnomAD3 genomes AF: 0.00000736 AC: 1 AN: 135856 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000224

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000425 AC: 9 AN: 211648 AF XY: 0.0000530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000576

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000662 AC: 9 AN: 1360452 Hom.: 1 Cov.: 31 AF XY: 0.00000738 AC XY: 5 AN XY: 677570

African (AFR) AF: 0.00 AC: 0 AN: 32410

American (AMR) AF: 0.00 AC: 0 AN: 40550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.000240 AC: 9 AN: 37454

South Asian (SAS) AF: 0.00 AC: 0 AN: 80516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1032518

Other (OTH) AF: 0.00 AC: 0 AN: 56974

GnomAD4 genome AF: 0.00000735 AC: 1 AN: 135976 Hom.: 0 Cov.: 25 AF XY: 0.0000153 AC XY: 1 AN XY: 65526

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

African (AFR) AF: 0.00 AC: 0 AN: 38660

American (AMR) AF: 0.00 AC: 0 AN: 13498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3196

East Asian (EAS) AF: 0.000225 AC: 1 AN: 4442

South Asian (SAS) AF: 0.00 AC: 0 AN: 3772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61066

Other (OTH) AF: 0.00 AC: 0 AN: 1862

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000594 AC: 7

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	0.23
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.067	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.32
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.24
MutPred		0.61		Gain of catalytic residue at V225 (P = 0.0056)
MVP		0.49
MPC		1.4
ClinPred		0.26	T
GERP RS		2.5
Varity_R		0.65
gMVP		0.082
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs563007702; hg19: chr1-248813513;