rs12422210

Variant names:

• chr11-17641869-G-A
• rs12422210
• NM_001292063.2:c.8213G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:4
• Conservation: PhyloP100: 1.47
• Publications: 13 publications found

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]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.8213G>A	p.Arg2738Gln	missense_variant	Exon 52 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.8249G>A	p.Arg2750Gln	missense_variant	Exon 51 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.8213G>A	p.Arg2738Gln	missense_variant	Exon 52 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.8249G>A	p.Arg2750Gln	missense_variant	Exon 51 of 55	5		ENSP00000382323.2

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

GnomAD2 exomes AF: 0.129 AC: 18943 AN: 146980 AF XY: 0.136

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 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

African (AFR) AF: 0.0248 AC: 783 AN: 31588

American (AMR) AF: 0.0736 AC: 2620 AN: 35592

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3409 AN: 25098

East Asian (EAS) AF: 0.000420 AC: 15 AN: 35730

South Asian (SAS) AF: 0.170 AC: 13388 AN: 78960

European-Finnish (FIN) AF: 0.151 AC: 7253 AN: 48096

Middle Eastern (MID) AF: 0.144 AC: 820 AN: 5688

European-Non Finnish (NFE) AF: 0.178 AC: 191394 AN: 1077314

Other (OTH) AF: 0.144 AC: 8320 AN: 57924

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

African (AFR) AF: 0.0309 AC: 1283 AN: 41498

American (AMR) AF: 0.101 AC: 1550 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3470

East Asian (EAS) AF: 0.00233 AC: 12 AN: 5156

South Asian (SAS) AF: 0.154 AC: 743 AN: 4824

European-Finnish (FIN) AF: 0.145 AC: 1534 AN: 10586

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11887 AN: 67958

Other (OTH) AF: 0.118 AC: 249 AN: 2108

Alfa AF: 0.143 Hom.: 2532

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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;.
PhyloP100		1.5
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12422210; hg19: chr11-17663416; COSMIC: COSV107428858; COSMIC: COSV107428858;