rs188527711

chr11-17612217-G-Achr11-17612217-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001292063.2(OTOG):c.6179G>A(p.Arg2060His) variant causes a missense change. The variant allele was found at a frequency of 0.00112 in 1,549,366 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. R2060L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.92

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018020421).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.6179G>A	p.Arg2060His	missense_variant	37/56	ENST00000399397.6
OTOG	NM_001277269.2	c.6215G>A	p.Arg2072His	missense_variant	36/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.6179G>A	p.Arg2060His	missense_variant	37/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.6215G>A	p.Arg2072His	missense_variant	36/55	5		A2
OTOG	ENST00000342528.2	n.3517G>A		non_coding_transcript_exon_variant	13/22	2

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000798 AC: 118 AN: 147896 Hom.: 0 AF XY: 0.000752 AC XY: 60 AN XY: 79740

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.000692

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000371

Gnomad SAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.000697

GnomAD4 exome AF: 0.00115 AC: 1607 AN: 1397102 Hom.: 2 Cov.: 31 AF XY: 0.00117 AC XY: 804 AN XY: 689148

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.000168

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.0000638

Gnomad4 NFE exome AF: 0.00136

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74464

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.000880

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.000379 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign in association with hearing loss to our knowledge; This variant is associated with the following publications: (PMID: 28050010) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2072 of the OTOG protein (p.Arg2072His). This variant is present in population databases (rs188527711, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 451001). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 10, 2017

The p.Arg2072His variant in OTOG has not been previously reported in individuals with hearing loss but has been identified in 0.14% (93/66920) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs188527711). Although this variant has been seen in the general popu lation, its frequency is not high enough to rule out a pathogenic role. Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In summary, the clinical significance of the p.Arg2072His variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 18B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.38
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.67	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.20
Sift	Benign	0.039	D;.
Sift4G	Benign	0.072	T;T
Vest4		0.33
MVP		0.27
ClinPred		0.043	T
GERP RS		4.5
Varity_R		0.065
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs188527711; hg19: chr11-17633764;