chr12-80355740-C-T

Position:

• chr12-80355740-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378609.3(OTOGL):​c.5598C>T​(p.Cys1866=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,611,732 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (22 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.995

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-80355740-C-T is Benign according to our data. Variant chr12-80355740-C-T is described in ClinVar as [Benign]. Clinvar id is 226958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.995 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00904 (1376/152202) while in subpopulation AFR AF= 0.0275 (1142/41522). AF 95% confidence interval is 0.0262. There are 12 homozygotes in gnomad4. There are 654 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.5598C>T	p.Cys1866=	synonymous_variant	47/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.5598C>T	p.Cys1866=	synonymous_variant	47/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.5463C>T	p.Cys1821=	synonymous_variant	51/63
OTOGL	ENST00000298820.7	c.900C>T	p.Cys300=	synonymous_variant	8/18	5

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1367 AN: 152084 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00393 AC: 963 AN: 244946 Hom.: 6 AF XY: 0.00325 AC XY: 433 AN XY: 133044

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.0152

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000548

Gnomad OTH exome AF: 0.00301

GnomAD4 exome AF: 0.00159 AC: 2320 AN: 1459530 Hom.: 22 Cov.: 31 AF XY: 0.00147 AC XY: 1065 AN XY: 725984

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.00236

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.00913

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000251

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.00904 AC: 1376 AN: 152202 Hom.: 12 Cov.: 32 AF XY: 0.00879 AC XY: 654 AN XY: 74408

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.0151

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00482 Hom.: 6

Bravo AF: 0.0106

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Cys1857Cys in exon 46 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 2.4% (92/3756) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs61734095). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.6
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61734095; hg19: chr12-80749520;