chr11-124383227-C-T

Position:

• chr11-124383227-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001005468.2(OR8B2):​c.117G>A​(p.Met39Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,613,926 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: OR8B2 NM_001005468.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20

Genes affected

OR8B2 (HGNC:8471): (olfactory receptor family 8 subfamily B 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00525409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR8B2	NM_001005468.2	c.117G>A	p.Met39Ile	missense_variant	2/2	ENST00000641451.2
OR8B2	XM_017017535.3	c.117G>A	p.Met39Ile	missense_variant	3/3
OR8B2	XM_017017536.2	c.117G>A	p.Met39Ile	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR8B2	ENST00000641451.2	c.117G>A	p.Met39Ile	missense_variant	2/2		NM_001005468.2	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152180 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251132 Hom.: 1 AF XY: 0.000184 AC XY: 25 AN XY: 135720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000109 AC: 160 AN: 1461628 Hom.: 1 Cov.: 44 AF XY: 0.000103 AC XY: 75 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152298 Hom.: 0 Cov.: 34 AF XY: 0.000148 AC XY: 11 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000411 Hom.: 1

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2021

The c.117G>A (p.M39I) alteration is located in exon 1 (coding exon 1) of the OR8B2 gene. This alteration results from a G to A substitution at nucleotide position 117, causing the methionine (M) at amino acid position 39 to be replaced by an isoleucine (I). 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	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.6
DANN	Benign	0.90
DEOGEN2	Benign	0.0018	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.31	.;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.085	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.67	.;N
REVEL	Benign	0.056
Sift	Benign	0.087	.;T
Sift4G	Benign	0.065	.;T
Polyphen		0.0	B;B
Vest4		0.042
MutPred		0.37		Gain of glycosylation at T38 (P = 0.1246);Gain of glycosylation at T38 (P = 0.1246);
MVP		0.15
MPC		0.55
ClinPred		0.012	T
GERP RS		1.2
Varity_R		0.13
gMVP		0.14

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: rs202110730; hg19: chr11-124253123; COSMIC: COSV104691425;