rs567966154

chr11-17640936-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001292063.2(OTOG):c.8035C>T(p.Arg2679Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000845 in 1,548,288 control chromosomes in the GnomAD database, including 5 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. R2679H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.37

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009334862).
• BP6: Variant 11-17640936-C-T is Benign according to our data. Variant chr11-17640936-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17640936-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.8035C>T	p.Arg2679Cys	missense_variant	51/56	ENST00000399397.6
OTOG	NM_001277269.2	c.8071C>T	p.Arg2691Cys	missense_variant	50/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.8035C>T	p.Arg2679Cys	missense_variant	51/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8071C>T	p.Arg2691Cys	missense_variant	50/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152226 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000895 AC: 130 AN: 145180 Hom.: 0 AF XY: 0.000727 AC XY: 57 AN XY: 78444

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000937

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000928

Gnomad SAS exome AF: 0.0000889

Gnomad FIN exome AF: 0.0000720

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.000943

GnomAD4 exome AF: 0.000500 AC: 698 AN: 1395944 Hom.: 1 Cov.: 35 AF XY: 0.000453 AC XY: 312 AN XY: 688592

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.000326

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152344 Hom.: 4 Cov.: 32 AF XY: 0.00384 AC XY: 286 AN XY: 74486

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00202 Hom.: 1

Bravo AF: 0.00457

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000746 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2017

p.Arg2691Cys in exon 50 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 1.3% (193/15206) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs567966154). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.58	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.041	D;D
Vest4		0.47
MVP		0.48
ClinPred		0.036	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.75

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: rs567966154; hg19: chr11-17662483;