NM_001292063.2:c.6515G>T

Variant names:

• chr11-17613688-G-T
• rs555068328
• NM_001292063.2:c.6515G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001292063.2(OTOG):​c.6515G>T​(p.Arg2172Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000501 in 1,398,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2172H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17613688-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505049.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

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.6515G>T	p.Arg2172Leu	missense	Exon 39 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.6551G>T	p.Arg2184Leu	missense	Exon 38 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.6515G>T	p.Arg2172Leu	missense	Exon 39 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.6551G>T	p.Arg2184Leu	missense	Exon 38 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.3853G>T		non_coding_transcript_exon	Exon 15 of 22

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000666 AC: 1 AN: 150240 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000501 AC: 7 AN: 1398482 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 689744

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35706

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000649 AC: 7 AN: 1078950

Other (OTH) AF: 0.00 AC: 0 AN: 58082

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.7
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Vest4		0.72
MutPred		0.72		Gain of ubiquitination at K2188 (P = 0.0619)
MVP		0.73
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.82
Mutation Taster		=66/34	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: rs555068328; hg19: chr11-17635235;