rs555614943

Variant names:

• chr11-17638545-C-T
• rs555614943
• NM_001292063.2:c.7890C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001292063.2(OTOG):​c.7890C>T​(p.Ser2630Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000426 in 1,550,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.270
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-17638545-C-T is Benign according to our data. Variant chr11-17638545-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.27 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. 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
	OTOG	NM_001292063.2	MANE Select	c.7890C>T	p.Ser2630Ser	synonymous	Exon 48 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.7926C>T	p.Ser2642Ser	synonymous	Exon 47 of 55	NP_001264198.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.7890C>T	p.Ser2630Ser	synonymous	Exon 48 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.7926C>T	p.Ser2642Ser	synonymous	Exon 47 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.4802C>T		non_coding_transcript_exon	Exon 21 of 22

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000809 AC: 12 AN: 148346 AF XY: 0.0000626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000927

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000422 AC: 59 AN: 1398036 Hom.: 0 Cov.: 30 AF XY: 0.0000392 AC XY: 27 AN XY: 689558

African (AFR) AF: 0.0000316 AC: 1 AN: 31598

American (AMR) AF: 0.000364 AC: 13 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35736

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48094

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5696

European-Non Finnish (NFE) AF: 0.0000278 AC: 30 AN: 1078836

Other (OTH) AF: 0.000103 AC: 6 AN: 57984

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74480

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	6.8
DANN	Benign	0.75
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism

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: rs555614943; hg19: chr11-17660092;