rs2034528

Positions:

• chr12-80358880-A-G
• chr12-80358880-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.6247A>G​(p.Ile2083Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.929 in 1,505,062 control chromosomes in the GnomAD database, including 649,613 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67607 hom., cov: 32)
  • Exomes 𝑓: 0.93 (582006 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.553

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.47368E-7).
• BP6: Variant 12-80358880-A-G is Benign according to our data. Variant chr12-80358880-A-G is described in ClinVar as [Benign]. Clinvar id is 226966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80358880-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.6247A>G	p.Ile2083Val	missense_variant	52/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.6247A>G	p.Ile2083Val	missense_variant	52/59	5	NM_001378609.3	ENSP00000447211.2

Frequencies

GnomAD3 genomes AF: 0.942 AC: 143322 AN: 152162 Hom.: 67568 Cov.: 32

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.941

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.973

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.934

GnomAD3 exomes AF: 0.941 AC: 139151 AN: 147890 Hom.: 65523 AF XY: 0.939 AC XY: 73229 AN XY: 77972

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.957

Gnomad ASJ exome AF: 0.895

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.949

Gnomad FIN exome AF: 0.971

Gnomad NFE exome AF: 0.921

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.927 AC: 1254466 AN: 1352782 Hom.: 582006 Cov.: 34 AF XY: 0.927 AC XY: 620823 AN XY: 669428

Gnomad4 AFR exome AF: 0.959

Gnomad4 AMR exome AF: 0.955

Gnomad4 ASJ exome AF: 0.893

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.948

Gnomad4 FIN exome AF: 0.970

Gnomad4 NFE exome AF: 0.921

Gnomad4 OTH exome AF: 0.929

GnomAD4 genome AF: 0.942 AC: 143416 AN: 152280 Hom.: 67607 Cov.: 32 AF XY: 0.944 AC XY: 70315 AN XY: 74452

Gnomad4 AFR AF: 0.960

Gnomad4 AMR AF: 0.941

Gnomad4 ASJ AF: 0.901

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.947

Gnomad4 FIN AF: 0.973

Gnomad4 NFE AF: 0.924

Gnomad4 OTH AF: 0.935

Alfa AF: 0.923 Hom.: 91338

Bravo AF: 0.941

TwinsUK AF: 0.921 AC: 3415

ALSPAC AF: 0.927 AC: 3571

ESP6500AA AF: 0.959 AC: 4160

ESP6500EA AF: 0.924 AC: 7815

ExAC AF: 0.928 AC: 76951

Asia WGS AF: 0.976 AC: 3388 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 11, 2015	Ile2074Val in exon 51 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 7.6% (641/8456) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2034528). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.8
DANN	Benign	0.29
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.16	T;.;T
MetaRNN	Benign	6.5e-7	T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.50	.;.;N
REVEL	Benign	0.026
Sift	Benign	1.0	.;.;T
Sift4G	Benign	1.0	.;.;T
Vest4		0.058
MPC		0.021
ClinPred		0.00015	T
GERP RS		0.35
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2034528; hg19: chr12-80752660;