rs12422210

Positions:

• chr11-17641869-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.8213G>A​(p.Arg2738Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,548,102 control chromosomes in the GnomAD database, including 21,575 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2738W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1337 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20238 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.47

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.726384E-4).
• BP6: Variant 11-17641869-G-A is Benign according to our data. Variant chr11-17641869-G-A is described in ClinVar as [Benign]. Clinvar id is 226916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17641869-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.8213G>A	p.Arg2738Gln	missense_variant	52/56	ENST00000399397.6
OTOG	NM_001277269.2	c.8249G>A	p.Arg2750Gln	missense_variant	51/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.8213G>A	p.Arg2738Gln	missense_variant	52/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8249G>A	p.Arg2750Gln	missense_variant	51/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17795 AN: 151994 Hom.: 1335 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.129 AC: 18943 AN: 146980 Hom.: 1526 AF XY: 0.136 AC XY: 10784 AN XY: 79224

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.0687

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.000650

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.163 AC: 228002 AN: 1395990 Hom.: 20238 Cov.: 32 AF XY: 0.164 AC XY: 112763 AN XY: 688574

Gnomad4 AFR exome AF: 0.0248

Gnomad4 AMR exome AF: 0.0736

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.000420

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.117 AC: 17787 AN: 152112 Hom.: 1337 Cov.: 32 AF XY: 0.115 AC XY: 8557 AN XY: 74352

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.00233

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.118

Alfa AF: 0.154 Hom.: 1858

Bravo AF: 0.109

TwinsUK AF: 0.180 AC: 666

ALSPAC AF: 0.173 AC: 668

ExAC AF: 0.124 AC: 2593

Asia WGS AF: 0.0730 AC: 256 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg2750Gln in exon 51 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 25.9% (44/170) of European American chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi .nlm.nih.gov/projects/SNP; dbSNP rs12422210). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.00067	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.19	N;.
REVEL	Benign	0.016
Sift	Benign	0.42	T;.
Sift4G	Benign	0.19	T;T
Vest4		0.061
ClinPred		0.0057	T
GERP RS		1.6
Varity_R		0.029
gMVP		0.26

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: rs12422210; hg19: chr11-17663416;