NM_001378609.3:c.6156C>T

Variant names:

• chr12-80358705-C-T
• rs34323912
• NM_001378609.3:c.6156C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378609.3(OTOGL):​c.6156C>T​(p.Leu2052Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,613,086 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (17 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.817
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.013).
• BP6: Variant 12-80358705-C-T is Benign according to our data. Variant chr12-80358705-C-T is described in ClinVar as Benign. ClinVar VariationId is 226964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.817 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00782 (1190/152214) while in subpopulation AFR AF = 0.0256 (1064/41536). AF 95% confidence interval is 0.0243. There are 15 homozygotes in GnomAd4. There are 577 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.6156C>T	p.Leu2052Leu	synonymous	Exon 51 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.6156C>T	p.Leu2052Leu	synonymous	Exon 54 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.6156C>T	p.Leu2052Leu	synonymous	Exon 51 of 59	NP_775862.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.6156C>T	p.Leu2052Leu	synonymous	Exon 51 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.6021C>T	p.Leu2007Leu	synonymous	Exon 55 of 63	ENSP00000496036.1
	OTOGL	ENST00000298820.7	TSL:5	c.1455C>T	p.Leu485Leu	synonymous	Exon 12 of 18	ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.00780 AC: 1186 AN: 152096 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00215 AC: 533 AN: 247952 AF XY: 0.00158

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000244

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.000982 AC: 1434 AN: 1460872 Hom.: 17 Cov.: 32 AF XY: 0.000856 AC XY: 622 AN XY: 726752

African (AFR) AF: 0.0276 AC: 924 AN: 33438

American (AMR) AF: 0.00239 AC: 107 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5762

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1111384

Other (OTH) AF: 0.00295 AC: 178 AN: 60346

GnomAD4 genome AF: 0.00782 AC: 1190 AN: 152214 Hom.: 15 Cov.: 32 AF XY: 0.00775 AC XY: 577 AN XY: 74424

African (AFR) AF: 0.0256 AC: 1064 AN: 41536

American (AMR) AF: 0.00530 AC: 81 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68000

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00332 Hom.: 1

Bravo AF: 0.00875

Asia WGS AF: 0.00231 AC: 8 AN: 3474

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	OTOGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.7
DANN	Benign	0.64
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34323912; hg19: chr12-80752485;