Genetic Variant NM_001005522.2:c.274C>T (chr1-247921291-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001005522.2(OR2T8):c.274C>T(p.Arg92Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.0000085 ( 0 hom., cov: 15)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OR2T8
NM_001005522.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.74

Publications

4 publications found

Variant links:

Genes affected

OR2T8 (HGNC:15020): (olfactory receptor family 2 subfamily T member 8) 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]

OR2T8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037896335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2T8	NM_001005522.2 link	c.274C>T	p.Arg92Cys	missense_variant	Exon 2 of 2	ENST00000641945.2	NP_001005522.1	A6NH00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2T8	ENST00000641945.2 link	c.274C>T	p.Arg92Cys	missense_variant	Exon 2 of 2		NM_001005522.2	ENSP00000493286.1		A6NH00

Frequencies

GnomAD3 genomes

AF:

0.00000848

AC:

AN:

117914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000343

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000638

AC:

AN:

141052

AF XY:

0.0000546

show subpopulations

Gnomad AFR exome

AF:

0.000426

Gnomad AMR exome

AF:

0.0000423

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000122

AC:

AN:

1144424

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

575868

show subpopulations

African (AFR)

AF:

0.000188

AC:

AN:

26570

American (AMR)

AF:

0.0000277

AC:

AN:

36062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21596

East Asian (EAS)

AF:

0.00

AC:

AN:

36024

South Asian (SAS)

AF:

0.0000433

AC:

AN:

69282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3476

European-Non Finnish (NFE)

AF:

0.00000470

AC:

AN:

851822

Other (OTH)

AF:

0.0000202

AC:

AN:

49494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000848

AC:

AN:

117914

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

55234

show subpopulations

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

African (AFR)

AF:

0.0000343

AC:

AN:

29130

American (AMR)

AF:

0.00

AC:

AN:

10520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3090

East Asian (EAS)

AF:

0.00

AC:

AN:

4224

South Asian (SAS)

AF:

0.00

AC:

AN:

2912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58106

Other (OTH)

AF:

0.00

AC:

AN:

1478

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 12, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.274C>T (p.R92C) alteration is located in exon 1 (coding exon 1) of the OR2T8 gene. This alteration results from a C to T substitution at nucleotide position 274, causing the arginine (R) at amino acid position 92 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

8.7

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0048

T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0077

LIST_S2

Benign

0.75

.;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

L;L

PhyloP100

-1.7

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.56

.;N

REVEL

Benign

0.081

Sift

Benign

0.093

.;T

Sift4G

Uncertain

0.048

.;D

Polyphen

0.97

D;D

Vest4

0.11

MVP

0.15

ClinPred

0.037

GERP RS

-1.8

Varity_R

0.074

gMVP

0.095

Mutation Taster

=98/2

polymorphism

(source)

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

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NM_001005522.2:c.274C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over