rs142799217

Variant names:

• chr11-17631882-G-A
• rs142799217
• NM_001292063.2:c.6893G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001292063.2(OTOG):​c.6893G>A​(p.Arg2298His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,550,382 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.29
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010238647).
• BP6: Variant 11-17631882-G-A is Benign according to our data. Variant chr11-17631882-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229098.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00198 (302/152330) while in subpopulation AFR AF = 0.00683 (284/41574). AF 95% confidence interval is 0.00618. There are 0 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.6893G>A	p.Arg2298His	missense	Exon 41 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.6929G>A	p.Arg2310His	missense	Exon 40 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.6893G>A	p.Arg2298His	missense	Exon 41 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.6929G>A	p.Arg2310His	missense	Exon 40 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.4231G>A		non_coding_transcript_exon	Exon 17 of 22

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 293 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00663

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000525 AC: 78 AN: 148628 AF XY: 0.000437

Gnomad AFR exome AF: 0.00857

Gnomad AMR exome AF: 0.000692

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000195 AC: 272 AN: 1398052 Hom.: 2 Cov.: 32 AF XY: 0.000173 AC XY: 119 AN XY: 689554

African (AFR) AF: 0.00684 AC: 216 AN: 31598

American (AMR) AF: 0.000728 AC: 26 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35738

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47970

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5666

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1078974

Other (OTH) AF: 0.000345 AC: 20 AN: 57986

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74482

African (AFR) AF: 0.00683 AC: 284 AN: 41574

American (AMR) AF: 0.000588 AC: 9 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000824 Hom.: 0

Bravo AF: 0.00225

ExAC AF: 0.000248 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.074	T
Sift4G	Uncertain	0.027	D
Vest4		0.21
MVP		0.60
ClinPred		0.066	T
GERP RS		4.8
Varity_R		0.060
gMVP		0.35
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs142799217; hg19: chr11-17653429;