chr11-17645848-G-A

Variant names:

• chr11-17645848-G-A
• rs542151771
• NM_001292063.2:c.8646G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):​c.8646G>A​(p.Leu2882Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,550,798 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (4 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.35
• 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]

LINC02729 (HGNC:54246): (long intergenic non-protein coding RNA 2729)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-17645848-G-A is Benign according to our data. Variant chr11-17645848-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000836 (1169/1398552) while in subpopulation AMR AF = 0.00272 (97/35706). AF 95% confidence interval is 0.00228. There are 4 homozygotes in GnomAdExome4. There are 541 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.8646G>A	p.Leu2882Leu	synonymous	Exon 56 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.8682G>A	p.Leu2894Leu	synonymous	Exon 55 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.8646G>A	p.Leu2882Leu	synonymous	Exon 56 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.8682G>A	p.Leu2894Leu	synonymous	Exon 55 of 55	ENSP00000382323.2	Q6ZRI0-1
	LINC02729	ENST00000849122.1		n.195+589C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000965 AC: 145 AN: 150224 AF XY: 0.000743

Gnomad AFR exome AF: 0.000145

Gnomad AMR exome AF: 0.00236

Gnomad ASJ exome AF: 0.000238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000591

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00389

GnomAD4 exome AF: 0.000836 AC: 1169 AN: 1398552 Hom.: 4 Cov.: 32 AF XY: 0.000784 AC XY: 541 AN XY: 689800

African (AFR) AF: 0.000222 AC: 7 AN: 31598

American (AMR) AF: 0.00272 AC: 97 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.000199 AC: 5 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79236

European-Finnish (FIN) AF: 0.000145 AC: 7 AN: 48300

Middle Eastern (MID) AF: 0.00228 AC: 13 AN: 5698

European-Non Finnish (NFE) AF: 0.000912 AC: 984 AN: 1079026

Other (OTH) AF: 0.000896 AC: 52 AN: 58068

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152246 Hom.: 1 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74378

African (AFR) AF: 0.000217 AC: 9 AN: 41470

American (AMR) AF: 0.000785 AC: 12 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000900 Hom.: 0

Bravo AF: 0.000688

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	not specified (1)
-	-	1	OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.9
DANN	Benign	0.79
PhyloP100		1.4
Mutation Taster		=95/5	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: rs542151771; hg19: chr11-17667395;