rs568549806

chr11-17631896-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001292063.2(OTOG):c.6907C>T(p.Arg2303Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,550,218 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2303H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.559

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014726251).
• BP6: Variant 11-17631896-C-T is Benign according to our data. Variant chr11-17631896-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 229099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.6907C>T	p.Arg2303Cys	missense_variant	41/56	ENST00000399397.6
OTOG	NM_001277269.2	c.6943C>T	p.Arg2315Cys	missense_variant	40/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.6907C>T	p.Arg2303Cys	missense_variant	41/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.6943C>T	p.Arg2315Cys	missense_variant	40/55	5		A2
OTOG	ENST00000342528.2	n.4245C>T		non_coding_transcript_exon_variant	17/22	2

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00115 AC: 171 AN: 148548 Hom.: 1 AF XY: 0.00115 AC XY: 92 AN XY: 80002

Gnomad AFR exome AF: 0.000295

Gnomad AMR exome AF: 0.000977

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00110 AC: 1543 AN: 1397876 Hom.: 2 Cov.: 32 AF XY: 0.00111 AC XY: 766 AN XY: 689468

Gnomad4 AFR exome AF: 0.000443

Gnomad4 AMR exome AF: 0.000868

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000442

Gnomad4 FIN exome AF: 0.00284

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74494

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000990

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.000767 AC: 19

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2021	See Variant Classification Assertion Criteria. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 12, 2018

p.Arg2315Cys in exon 40 of OTOG: This variant is classified as likely benign bec ause it has been identified in 0.3% (59/19838) of European Finnish chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs568549806). ACMG criteria applied: PP3; BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.81	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.4	D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.014	D;D
Vest4		0.27
MVP		0.72
ClinPred		0.048	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs568549806; hg19: chr11-17653443;