rs7936324

Variant names:

• chr11-17594057-C-T
• rs7936324
• NM_001292063.2:c.3299C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17594057-C-T
• chr11-17594057-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.3299C>T​(p.Ala1100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,550,468 control chromosomes in the GnomAD database, including 760 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1100A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.040 (436 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (324 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.92
• Publications: 3 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), 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=0.0024787784).
• BP6: Variant 11-17594057-C-T is Benign according to our data. Variant chr11-17594057-C-T is described in ClinVar as Benign. ClinVar VariationId is 226883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

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.3299C>T	p.Ala1100Val	missense	Exon 28 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.3335C>T	p.Ala1112Val	missense	Exon 27 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.3299C>T	p.Ala1100Val	missense	Exon 28 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.3335C>T	p.Ala1112Val	missense	Exon 27 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.664C>T		non_coding_transcript_exon	Exon 5 of 22

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6061 AN: 152072 Hom.: 436 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.00837 AC: 1248 AN: 149190 AF XY: 0.00665

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.00761

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.0000927

Gnomad FIN exome AF: 0.0000595

Gnomad NFE exome AF: 0.000636

Gnomad OTH exome AF: 0.00695

GnomAD4 exome AF: 0.00423 AC: 5920 AN: 1398278 Hom.: 324 Cov.: 32 AF XY: 0.00375 AC XY: 2583 AN XY: 689658

African (AFR) AF: 0.140 AC: 4432 AN: 31598

American (AMR) AF: 0.00829 AC: 296 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 19 AN: 25182

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

South Asian (SAS) AF: 0.000757 AC: 60 AN: 79234

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 48166

Middle Eastern (MID) AF: 0.00843 AC: 48 AN: 5696

European-Non Finnish (NFE) AF: 0.000465 AC: 502 AN: 1078968

Other (OTH) AF: 0.00967 AC: 561 AN: 57992

GnomAD4 genome AF: 0.0399 AC: 6068 AN: 152190 Hom.: 436 Cov.: 32 AF XY: 0.0381 AC XY: 2836 AN XY: 74402

African (AFR) AF: 0.137 AC: 5704 AN: 41498

American (AMR) AF: 0.0147 AC: 225 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68010

Other (OTH) AF: 0.0327 AC: 69 AN: 2112

Alfa AF: 0.0313 Hom.: 243

Bravo AF: 0.0459

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00790 AC: 165

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	0.099
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		1.9
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.030
Sift	Benign	0.15	T
Sift4G	Benign	0.099	T
Vest4		0.092
MVP		0.15
ClinPred		0.018	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.42
Mutation Taster		=99/1	polymorphism (auto)

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: rs7936324; hg19: chr11-17615604; COSMIC: COSV61130527;