rs61995750

Positions:

• chr11-17638480-C-A

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.7825C>A​(p.Gln2609Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,550,110 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2609L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.13

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=0.008367062).
• BP6: Variant 11-17638480-C-A is Benign according to our data. Variant chr11-17638480-C-A is described in ClinVar as [Benign]. Clinvar id is 227799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17638480-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00454 (691/152338) while in subpopulation AFR AF= 0.0153 (634/41568). AF 95% confidence interval is 0.0143. There are 7 homozygotes in gnomad4. There are 329 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7825C>A	p.Gln2609Lys	missense_variant	48/56	ENST00000399397.6
OTOG	NM_001277269.2	c.7861C>A	p.Gln2621Lys	missense_variant	47/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7825C>A	p.Gln2609Lys	missense_variant	48/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7861C>A	p.Gln2621Lys	missense_variant	47/55	5		A2
OTOG	ENST00000342528.2	n.4737C>A		non_coding_transcript_exon_variant	21/22	2

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 691 AN: 152220 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000984 AC: 146 AN: 148366 Hom.: 0 AF XY: 0.000789 AC XY: 63 AN XY: 79888

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000978

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000614

Gnomad NFE exome AF: 0.000201

Gnomad OTH exome AF: 0.000929

GnomAD4 exome AF: 0.000486 AC: 679 AN: 1397772 Hom.: 1 Cov.: 31 AF XY: 0.000439 AC XY: 303 AN XY: 689436

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.000314

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.00454 AC: 691 AN: 152338 Hom.: 7 Cov.: 32 AF XY: 0.00442 AC XY: 329 AN XY: 74494

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00213 Hom.: 1

Bravo AF: 0.00523

ExAC AF: 0.000673 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 29, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2017

p.Gln2621Lys in exon 47 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 1.5% (232/15266) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs61995750). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0084	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.090	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.70	N;.
REVEL	Benign	0.060
Sift	Benign	0.31	T;.
Sift4G	Benign	0.83	T;T
Vest4		0.20
MVP		0.10
ClinPred		0.0089	T
GERP RS		3.4
Varity_R		0.14
gMVP		0.58

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: rs61995750; hg19: chr11-17660027;