11-17641069-T-C

Position:

• chr11-17641069-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.8168T>C​(p.Leu2723Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,506,664 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2723L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (13 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017424077).
• BP6: Variant 11-17641069-T-C is Benign according to our data. Variant chr11-17641069-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17641069-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00596 (896/150232) while in subpopulation AFR AF= 0.0209 (857/40994). AF 95% confidence interval is 0.0197. There are 8 homozygotes in gnomad4. There are 410 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.8168T>C	p.Leu2723Pro	missense_variant	51/56	ENST00000399397.6
OTOG	NM_001277269.2	c.8204T>C	p.Leu2735Pro	missense_variant	50/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.8168T>C	p.Leu2723Pro	missense_variant	51/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8204T>C	p.Leu2735Pro	missense_variant	50/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 886 AN: 150108 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00339

GnomAD3 exomes AF: 0.00133 AC: 191 AN: 143506 Hom.: 1 AF XY: 0.00118 AC XY: 92 AN XY: 77724

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000945

GnomAD4 exome AF: 0.000665 AC: 902 AN: 1356432 Hom.: 13 Cov.: 36 AF XY: 0.000601 AC XY: 402 AN XY: 669226

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.000837

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000888

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000483

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00596 AC: 896 AN: 150232 Hom.: 8 Cov.: 32 AF XY: 0.00559 AC XY: 410 AN XY: 73362

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.00192

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000444

Gnomad4 OTH AF: 0.00336

Alfa AF: 0.00403 Hom.: 6

Bravo AF: 0.00662

ExAC AF: 0.000829 AC: 17

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 04, 2016

p.Leu2735Pro in exon 50 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 1.5% (12/792) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs180703235). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.17
Sift	Benign	0.15	T;T
Sift4G	Benign	0.21	T;T
Vest4		0.66
MVP		0.48
ClinPred		0.024	T
GERP RS		4.6
Varity_R		0.24
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs180703235; hg19: chr11-17662616;