rs2717482

Positions:

• chr12-80367685-G-A
• chr12-80367685-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378609.3(OTOGL):​c.6456G>A​(p.Thr2152=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.93 in 1,487,130 control chromosomes in the GnomAD database, including 644,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68545 hom., cov: 32)
  • Exomes 𝑓: 0.93 (575559 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.841

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 12-80367685-G-A is Benign according to our data. Variant chr12-80367685-G-A is described in ClinVar as [Benign]. Clinvar id is 226970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80367685-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.841 with no splicing effect.
• 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.6456G>A	p.Thr2152=	synonymous_variant	54/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.6456G>A	p.Thr2152=	synonymous_variant	54/59	5	NM_001378609.3	ENSP00000447211	P1

Frequencies

GnomAD3 genomes AF: 0.948 AC: 144249 AN: 152094 Hom.: 68493 Cov.: 32

Gnomad AFR AF: 0.982

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.910

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: 0.938

GnomAD3 exomes AF: 0.942 AC: 133550 AN: 141818 Hom.: 62944 AF XY: 0.938 AC XY: 71439 AN XY: 76142

Gnomad AFR exome AF: 0.984

Gnomad AMR exome AF: 0.955

Gnomad ASJ exome AF: 0.895

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.944

Gnomad FIN exome AF: 0.970

Gnomad NFE exome AF: 0.918

Gnomad OTH exome AF: 0.921

GnomAD4 exome AF: 0.928 AC: 1239245 AN: 1334918 Hom.: 575559 Cov.: 35 AF XY: 0.928 AC XY: 613494 AN XY: 660958

Gnomad4 AFR exome AF: 0.983

Gnomad4 AMR exome AF: 0.953

Gnomad4 ASJ exome AF: 0.903

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.947

Gnomad4 FIN exome AF: 0.970

Gnomad4 NFE exome AF: 0.921

Gnomad4 OTH exome AF: 0.931

GnomAD4 genome AF: 0.948 AC: 144358 AN: 152212 Hom.: 68545 Cov.: 32 AF XY: 0.951 AC XY: 70770 AN XY: 74422

Gnomad4 AFR AF: 0.982

Gnomad4 AMR AF: 0.944

Gnomad4 ASJ AF: 0.910

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.946

Gnomad4 FIN AF: 0.973

Gnomad4 NFE AF: 0.924

Gnomad4 OTH AF: 0.939

Alfa AF: 0.932 Hom.: 24232

Bravo AF: 0.948

Asia WGS AF: 0.978 AC: 3391 AN: 3466

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr2143Thr in exon 53 of OTOGL: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 7.9% (675/8584) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2717482). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.9
DANN	Benign	0.67

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: rs2717482; hg19: chr12-80761465; COSMIC: COSV54020811; COSMIC: COSV54020811;