rs61995750

Variant names:

• chr11-17638480-C-A
• rs61995750
• NM_001292063.2:c.7825C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17638480-C-A
• chr11-17638480-C-T

Variant summary

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

The ENST00000399397.6(OTOG):​c.7825C>A​(p.Gln2609Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,550,110 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2609L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: OTOG ENST00000399397.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.13
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008367062).
• BP6: Variant 11-17638480-C-A is Benign according to our data. Variant chr11-17638480-C-A is described in ClinVar as Benign. ClinVar VariationId is 227799.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 = 0.00454 (691/152338) while in subpopulation AFR AF = 0.0153 (634/41568). AF 95% confidence interval is 0.0143. There are 7 homozygotes in GnomAd4. There are 329 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.7825C>A	p.Gln2609Lys	missense	Exon 48 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.7861C>A	p.Gln2621Lys	missense	Exon 47 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.7825C>A	p.Gln2609Lys	missense	Exon 48 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.7861C>A	p.Gln2621Lys	missense	Exon 47 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.4737C>A		non_coding_transcript_exon	Exon 21 of 22

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 691 AN: 152220 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.000984 AC: 146 AN: 148366 AF XY: 0.000789

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000978

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000614

Gnomad NFE exome AF: 0.000201

Gnomad OTH exome AF: 0.000929

GnomAD4 exome AF: 0.000486 AC: 679 AN: 1397772 Hom.: 1 Cov.: 31 AF XY: 0.000439 AC XY: 303 AN XY: 689436

African (AFR) AF: 0.0143 AC: 452 AN: 31590

American (AMR) AF: 0.00123 AC: 44 AN: 35690

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

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

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79222

European-Finnish (FIN) AF: 0.000314 AC: 15 AN: 47726

Middle Eastern (MID) AF: 0.000877 AC: 5 AN: 5700

European-Non Finnish (NFE) AF: 0.0000908 AC: 98 AN: 1078940

Other (OTH) AF: 0.00110 AC: 64 AN: 57996

GnomAD4 genome AF: 0.00454 AC: 691 AN: 152338 Hom.: 7 Cov.: 32 AF XY: 0.00442 AC XY: 329 AN XY: 74494

African (AFR) AF: 0.0153 AC: 634 AN: 41568

American (AMR) AF: 0.00248 AC: 38 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68034

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00230 Hom.: 1

Bravo AF: 0.00523

ExAC AF: 0.000673 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.090	N
PhyloP100		1.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.060
Sift	Benign	0.31	T
Sift4G	Benign	0.83	T
Vest4		0.20
MVP		0.10
ClinPred		0.0089	T
GERP RS		3.4
Varity_R		0.14
gMVP		0.58
Mutation Taster		=97/3	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: rs61995750; hg19: chr11-17660027;