rs2717482

Variant names:

• chr12-80367685-G-A
• rs2717482
• NM_001378609.3:c.6456G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378609.3(OTOGL):​c.6456G>A​(p.Thr2152Thr) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T2152T) has been classified as Likely 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
• Publications: 18 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.019).
• BP6: Variant 12-80367685-G-A is Benign according to our data. Variant chr12-80367685-G-A is described in ClinVar as Benign. ClinVar VariationId is 226970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.6456G>A	p.Thr2152Thr	synonymous	Exon 54 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.6456G>A	p.Thr2152Thr	synonymous	Exon 57 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.6456G>A	p.Thr2152Thr	synonymous	Exon 54 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.6456G>A	p.Thr2152Thr	synonymous	Exon 54 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.6321G>A	p.Thr2107Thr	synonymous	Exon 58 of 63	ENSP00000496036.1
	OTOGL	ENST00000298820.7	TSL:5	c.1650G>A	p.Thr550Thr	synonymous	Exon 13 of 18	ENSP00000298820.3

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

GnomAD2 exomes AF: 0.942 AC: 133550 AN: 141818 AF XY: 0.938

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 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

African (AFR) AF: 0.983 AC: 26943 AN: 27410

American (AMR) AF: 0.953 AC: 23886 AN: 25052

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 18784 AN: 20794

East Asian (EAS) AF: 1.00 AC: 35196 AN: 35202

South Asian (SAS) AF: 0.947 AC: 64969 AN: 68594

European-Finnish (FIN) AF: 0.970 AC: 48294 AN: 49776

Middle Eastern (MID) AF: 0.857 AC: 4564 AN: 5326

European-Non Finnish (NFE) AF: 0.921 AC: 965348 AN: 1047702

Other (OTH) AF: 0.931 AC: 51261 AN: 55062

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

African (AFR) AF: 0.982 AC: 40795 AN: 41538

American (AMR) AF: 0.944 AC: 14410 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 3159 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5172

South Asian (SAS) AF: 0.946 AC: 4570 AN: 4830

European-Finnish (FIN) AF: 0.973 AC: 10326 AN: 10612

Middle Eastern (MID) AF: 0.853 AC: 249 AN: 292

European-Non Finnish (NFE) AF: 0.924 AC: 62838 AN: 68006

Other (OTH) AF: 0.939 AC: 1984 AN: 2112

Alfa AF: 0.935 Hom.: 35634

Bravo AF: 0.948

Asia WGS AF: 0.978 AC: 3391 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.9
DANN	Benign	0.67
PhyloP100		0.84
PromoterAI		-0.0016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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