11-17612217-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001292063.2(OTOG):c.6179G>T(p.Arg2060Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000818 in 1,549,256 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2060H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (2 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044306666).
• BP6: Variant 11-17612217-G-T is Benign according to our data. Variant chr11-17612217-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229097.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.6179G>T	p.Arg2060Leu	missense_variant	37/56	ENST00000399397.6
OTOG	NM_001277269.2	c.6215G>T	p.Arg2072Leu	missense_variant	36/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.6179G>T	p.Arg2060Leu	missense_variant	37/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.6215G>T	p.Arg2072Leu	missense_variant	36/55	5		A2
OTOG	ENST00000342528.2	n.3517G>T		non_coding_transcript_exon_variant	13/22	2

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000581 AC: 86 AN: 147896 Hom.: 1 AF XY: 0.000652 AC XY: 52 AN XY: 79740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000577

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000851 AC: 1189 AN: 1397106 Hom.: 2 Cov.: 31 AF XY: 0.000834 AC XY: 575 AN XY: 689150

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000644

Gnomad4 FIN exome AF: 0.0000213

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000328

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74338

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00208 AC: 8

ExAC AF: 0.000421 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 08, 2022	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2072 of the OTOG protein (p.Arg2072Leu). 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: 229097). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Arg2072Leu va riant in OTOG has now been identified by our laboratory in 2 Caucasian individua l with hearing loss; however, one of these individuals carried variants in a dif ferent gene that were sufficient to explain their hearing loss. This variant has also been identified in 0.1% (73/66920) of European chromosomes, including 1 ho mozygous individual, by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; rs188527711). Although this variant has been seen in the gene ral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. In summary, while the clinical s ignificance of the p.Arg2072Leu variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BP5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.012	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.84	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.3	N;.
REVEL	Benign	0.11
Sift	Benign	1.0	T;.
Sift4G	Benign	0.71	T;T
Vest4		0.31
MVP		0.43
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.11
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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; COSMIC: COSV61130152;