rs180703235

Variant names:

• chr11-17641069-T-C
• rs180703235
• NM_001292063.2:c.8168T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.8168T>C​(p.Leu2723Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,506,664 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2723L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (13 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.31
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017424077).
• BP6: Variant 11-17641069-T-C is Benign according to our data. Variant chr11-17641069-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00596 (896/150232) while in subpopulation AFR AF = 0.0209 (857/40994). AF 95% confidence interval is 0.0197. There are 8 homozygotes in GnomAd4. There are 410 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.8168T>C	p.Leu2723Pro	missense	Exon 51 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.8204T>C	p.Leu2735Pro	missense	Exon 50 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.8168T>C	p.Leu2723Pro	missense	Exon 51 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.8204T>C	p.Leu2735Pro	missense	Exon 50 of 55	ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 886 AN: 150108 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00339

GnomAD2 exomes AF: 0.00133 AC: 191 AN: 143506 AF XY: 0.00118

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000945

GnomAD4 exome AF: 0.000665 AC: 902 AN: 1356432 Hom.: 13 Cov.: 36 AF XY: 0.000601 AC XY: 402 AN XY: 669226

African (AFR) AF: 0.0237 AC: 724 AN: 30600

American (AMR) AF: 0.000837 AC: 29 AN: 34634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23808

East Asian (EAS) AF: 0.00 AC: 0 AN: 32048

South Asian (SAS) AF: 0.0000888 AC: 7 AN: 78848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38716

Middle Eastern (MID) AF: 0.00273 AC: 15 AN: 5490

European-Non Finnish (NFE) AF: 0.0000483 AC: 51 AN: 1056796

Other (OTH) AF: 0.00137 AC: 76 AN: 55492

GnomAD4 genome AF: 0.00596 AC: 896 AN: 150232 Hom.: 8 Cov.: 32 AF XY: 0.00559 AC XY: 410 AN XY: 73362

African (AFR) AF: 0.0209 AC: 857 AN: 40994

American (AMR) AF: 0.00192 AC: 29 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 4996

South Asian (SAS) AF: 0.00 AC: 0 AN: 4678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67566

Other (OTH) AF: 0.00336 AC: 7 AN: 2086

Alfa AF: 0.00291 Hom.: 17

Bravo AF: 0.00662

ExAC AF: 0.000829 AC: 17

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.17
Sift	Benign	0.15	T
Sift4G	Benign	0.21	T
Vest4		0.66
MVP		0.48
ClinPred		0.024	T
GERP RS		4.6
Varity_R		0.24
gMVP		0.77
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs180703235; hg19: chr11-17662616;