12-80267318-C-G

Position:

• chr12-80267318-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378609.3(OTOGL):​c.2456C>G​(p.Ser819Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign 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. S819L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23544818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.2456C>G	p.Ser819Trp	missense_variant	22/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.2456C>G	p.Ser819Trp	missense_variant	22/59	5	NM_001378609.3	ENSP00000447211	P1
OTOGL	ENST00000646859.1	c.2456C>G	p.Ser819Trp	missense_variant	27/63			ENSP00000496036

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370220 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 682868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.58e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.8	.;.;D
REVEL	Benign	0.15
Sift	Benign	0.092	.;.;T
Sift4G	Uncertain	0.0030	.;.;D
Vest4		0.61
MutPred		0.61		.;.;Loss of disorder (P = 0.0402);
MVP		0.14
MPC		0.12
ClinPred		0.94	D
GERP RS		2.6
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199855270; hg19: chr12-80661098;