rs199855270

Variant names:

• chr12-80267318-C-T
• rs199855270
• NM_001378609.3:c.2456C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-80267318-C-T
• chr12-80267318-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378609.3(OTOGL):​c.2456C>T​(p.Ser819Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,521,864 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S819P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.18
• Publications: 3 publications found

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0106340945).
• BP6: Variant 12-80267318-C-T is Benign according to our data. Variant chr12-80267318-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227815.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00119 (180/151666) while in subpopulation NFE AF = 0.00238 (162/67968). AF 95% confidence interval is 0.00208. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. 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
	OTOGL	NM_001378609.3	MANE Select	c.2456C>T	p.Ser819Leu	missense	Exon 22 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.2456C>T	p.Ser819Leu	missense	Exon 25 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.2456C>T	p.Ser819Leu	missense	Exon 22 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.2456C>T	p.Ser819Leu	missense	Exon 22 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.2456C>T	p.Ser819Leu	missense	Exon 27 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 180 AN: 151666 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000862

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000946 AC: 205 AN: 216752 AF XY: 0.00105

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.000533

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000680

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.000578

GnomAD4 exome AF: 0.00113 AC: 1543 AN: 1370198 Hom.: 3 Cov.: 28 AF XY: 0.00116 AC XY: 792 AN XY: 682854

African (AFR) AF: 0.0000647 AC: 2 AN: 30900

American (AMR) AF: 0.000195 AC: 8 AN: 41046

Ashkenazi Jewish (ASJ) AF: 0.000284 AC: 7 AN: 24664

East Asian (EAS) AF: 0.00 AC: 0 AN: 37410

South Asian (SAS) AF: 0.000332 AC: 26 AN: 78424

European-Finnish (FIN) AF: 0.00130 AC: 67 AN: 51540

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5550

European-Non Finnish (NFE) AF: 0.00133 AC: 1393 AN: 1043906

Other (OTH) AF: 0.000687 AC: 39 AN: 56758

GnomAD4 genome AF: 0.00119 AC: 180 AN: 151666 Hom.: 1 Cov.: 31 AF XY: 0.00111 AC XY: 82 AN XY: 74090

African (AFR) AF: 0.000121 AC: 5 AN: 41310

American (AMR) AF: 0.000132 AC: 2 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4804

European-Finnish (FIN) AF: 0.000862 AC: 9 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00238 AC: 162 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00162 Hom.: 3

Bravo AF: 0.000816

ESP6500AA AF: 0.000273 AC: 1

ESP6500EA AF: 0.00183 AC: 15

ExAC AF: 0.000979 AC: 118

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	OTOGL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.96
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.99	T
PhyloP100		2.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.021
Sift	Benign	0.51	T
Sift4G	Benign	0.11	T
Vest4		0.27
MVP		0.10
MPC		0.022
ClinPred		0.024	T
GERP RS		2.6
gMVP		0.45
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs199855270; hg19: chr12-80661098; COSMIC: COSV72005760; COSMIC: COSV72005760;