rs192234924

Positions:

• chr12-80257928-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001378609.3(OTOGL):​c.1815G>T​(p.Gln605His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,598,186 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00092 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.09

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02024138).
• BP6: Variant 12-80257928-G-T is Benign according to our data. Variant chr12-80257928-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227812.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.1815G>T	p.Gln605His	missense_variant	18/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.1815G>T	p.Gln605His	missense_variant	18/59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.1815G>T	p.Gln605His	missense_variant	23/63			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.2475G>T		non_coding_transcript_exon_variant	21/23

Frequencies

GnomAD3 genomes AF: 0.000921 AC: 140 AN: 152080 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000266 AC: 62 AN: 233246 Hom.: 1 AF XY: 0.000188 AC XY: 24 AN XY: 127506

Gnomad AFR exome AF: 0.00318

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000754 AC: 109 AN: 1445988 Hom.: 0 Cov.: 30 AF XY: 0.0000792 AC XY: 57 AN XY: 719676

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.000337

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000920 AC: 140 AN: 152198 Hom.: 2 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74406

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.00113

ESP6500AA AF: 0.00298 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000320 AC: 38

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2020	Reported as heterozygous in a patient with neonatal onset encephalopathy, brain atrophy with cerebellar malformation, and later-onset seizures who was also heterozygous for the Q1216H variant; however, this patient harbored a homozygous nonsense variant in the TBCK gene which the authors concluded was likely the causative variant (Chong et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27040692) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 13, 2017	p.Gln596His in exon 17 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (79/23656) of African chromos omes, including 2 homozygotes individual by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org; dbSNP rs192234924). -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The OTOGL p.Gln596His variant was identified in dbSNP (ID: rs192234924) and ClinVar (classified as likely benign by Invitae and Laboratory for Molecular Medicine) but was not identified in LOVD 3.0. The variant was identified in the literature in a family with TBCK-associated infantile syndromic encephalopathy; the OTOGL variant was not expected to contribute to the phenotype (Chong_2016_PMID:27040692). The variant was identified in control databases in 92 of 264632 chromosomes (2 homozygous) at a frequency of 0.0003477 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 78 of 23824 chromosomes (freq: 0.003274) and Latino in 14 of 34894 chromosomes (freq: 0.000401), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Gln596 residue is conserved in mammals and computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.59	T;.;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-0.88	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.4	.;.;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	.;.;D
Sift4G	Uncertain	0.0030	.;.;D
Vest4		0.71
MutPred		0.71		.;.;Loss of stability (P = 0.0866);
MVP		0.34
MPC		0.18
ClinPred		0.077	T
GERP RS		3.7
gMVP		0.66

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: rs192234924; hg19: chr12-80651708;