rs61730948

Variant names:

• chr11-17641918-C-T
• rs61730948
• NM_001292063.2:c.8262C>T

Variant summary

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

The ENST00000399397.6(OTOG):​c.8262C>T​(p.Phe2754Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,550,294 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (125 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (98 hom.)
• Consequence: OTOG ENST00000399397.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.15
• Publications: 0 publications found

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• 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 (BayesDel_noAF=-0.36).
• BP6: Variant 11-17641918-C-T is Benign according to our data. Variant chr11-17641918-C-T is described in ClinVar as Benign. ClinVar VariationId is 226918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399397.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.8262C>T	p.Phe2754Phe	synonymous	Exon 52 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.8298C>T	p.Phe2766Phe	synonymous	Exon 51 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.8262C>T	p.Phe2754Phe	synonymous	Exon 52 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.8298C>T	p.Phe2766Phe	synonymous	Exon 51 of 55	ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3114 AN: 152098 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00434 AC: 646 AN: 148748 AF XY: 0.00361

Gnomad AFR exome AF: 0.0743

Gnomad AMR exome AF: 0.00395

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000383

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00226 AC: 3153 AN: 1398078 Hom.: 98 Cov.: 33 AF XY: 0.00203 AC XY: 1401 AN XY: 689576

African (AFR) AF: 0.0753 AC: 2377 AN: 31574

American (AMR) AF: 0.00423 AC: 151 AN: 35676

Ashkenazi Jewish (ASJ) AF: 0.000676 AC: 17 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.000290 AC: 23 AN: 79220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48164

Middle Eastern (MID) AF: 0.00421 AC: 24 AN: 5696

European-Non Finnish (NFE) AF: 0.000235 AC: 253 AN: 1078854

Other (OTH) AF: 0.00531 AC: 308 AN: 57992

GnomAD4 genome AF: 0.0205 AC: 3119 AN: 152216 Hom.: 125 Cov.: 32 AF XY: 0.0193 AC XY: 1439 AN XY: 74434

African (AFR) AF: 0.0708 AC: 2940 AN: 41532

American (AMR) AF: 0.00686 AC: 105 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67988

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.00950 Hom.: 22

Bravo AF: 0.0233

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.6
DANN	Benign	0.75
PhyloP100		3.2
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs61730948; hg19: chr11-17663465;