Genetic Variant OTOGL:p.Cys2077Gly (chr12-80358862-T-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_001378609.3(OTOGL):c.6229T>G(p.Cys2077Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000195 in 1,521,632 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

OTOGL
NM_001378609.3 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 6.71

Publications

2 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 84B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 5: AlphaMissense, Cadd, Eigen, FATHMM_MKL, PROVEAN [when BayesDel_addAF, MetaRNN, MutationTaster was below the threshold]

BP6

Variant 12-80358862-T-G is Benign according to our data. Variant chr12-80358862-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227825.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00103 (157/152312) while in subpopulation AFR AF = 0.00346 (144/41586). AF 95% confidence interval is 0.003. There are 2 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOGL	NM_001378609.3	MANE Select	c.6229T>G	p.Cys2077Gly	missense splice_region	Exon 52 of 59	NP_001365538.2
OTOGL	NM_001378610.3		c.6229T>G	p.Cys2077Gly	missense splice_region	Exon 55 of 62	NP_001365539.2
OTOGL	NM_173591.7		c.6229T>G	p.Cys2077Gly	missense splice_region	Exon 52 of 59	NP_775862.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.6229T>G	p.Cys2077Gly	missense splice_region	Exon 52 of 59	ENSP00000447211.2
OTOGL	ENST00000646859.1		c.6094T>G	p.Cys2032Gly	missense splice_region	Exon 56 of 63	ENSP00000496036.1
OTOGL	ENST00000546620.5	TSL:2	n.485T>G		splice_region non_coding_transcript_exon	Exon 5 of 12

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

158

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00350

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000253

AC:

AN:

150204

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00343

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000329

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000102

AC:

139

AN:

1369320

Hom.:

Cov.:

AF XY:

0.0000945

AC XY:

AN XY:

677112

show subpopulations

African (AFR)

AF:

0.00267

AC:

AN:

31028

American (AMR)

AF:

0.000307

AC:

AN:

35818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25034

East Asian (EAS)

AF:

0.00

AC:

AN:

35586

South Asian (SAS)

AF:

0.00

AC:

AN:

78692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37776

Middle Eastern (MID)

AF:

0.000370

AC:

AN:

5402

European-Non Finnish (NFE)

AF:

0.0000301

AC:

AN:

1062690

Other (OTH)

AF:

0.000192

AC:

AN:

57294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152312

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00346

AC:

144

AN:

41586

American (AMR)

AF:

0.000589

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000361

Hom.:

Bravo

AF:

0.00106

ESP6500AA

AF:

0.00321

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 06, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported without a second variant in unrelated patients with hearing loss in published literature (PMID: 33136635); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33136635)

Apr 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cys2068Gly in exon 51 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (14/4362) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs145929269).

Inborn genetic diseases

Benign:1

Feb 15, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.33

PhyloP100

6.7

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-9.3

REVEL

Uncertain

0.34

Sift

Uncertain

0.012

Sift4G

Uncertain

0.013

Vest4

0.82

MVP

0.58

MPC

0.15

ClinPred

0.18

GERP RS

5.4

gMVP

0.98

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over