8-132024666-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080399.3(OC90):​c.1249G>A​(p.Gly417Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

OC90
NM_001080399.3 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.505
Variant links:
Genes affected
OC90 (HGNC:8100): (otoconin 90) Predicted to enable calcium ion binding activity and structural molecule activity. Predicted to be involved in otolith mineralization. Predicted to be located in extracellular region. Predicted to be active in extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.051403046).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OC90NM_001080399.3 linkuse as main transcriptc.1249G>A p.Gly417Arg missense_variant 14/14 ENST00000254627.4 NP_001073868.2 Q02509-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OC90ENST00000254627.4 linkuse as main transcriptc.1249G>A p.Gly417Arg missense_variant 14/142 NM_001080399.3 ENSP00000254627.3 Q02509-1
ENSG00000258417ENST00000262283.5 linkuse as main transcriptc.1885G>A p.Gly629Arg missense_variant 18/185 ENSP00000262283.5 I6L893

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000325
AC:
8
AN:
246164
Hom.:
0
AF XY:
0.0000522
AC XY:
7
AN XY:
133990
show subpopulations
Gnomad AFR exome
AF:
0.000266
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000658
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000180
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1460996
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
726756
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.000110
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 13, 2024The c.1249G>A (p.G417R) alteration is located in exon 14 (coding exon 13) of the OC90 gene. This alteration results from a G to A substitution at nucleotide position 1249, causing the glycine (G) at amino acid position 417 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
9.7
DANN
Benign
0.51
Eigen
Benign
-0.95
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.034
N
LIST_S2
Benign
0.45
T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.051
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.22
T
PROVEAN
Benign
1.2
N;N
REVEL
Benign
0.074
Sift
Benign
0.44
T;T
Sift4G
Benign
0.48
T;T
Vest4
0.070
MVP
0.099
MPC
0.0031
ClinPred
0.028
T
GERP RS
1.3
Varity_R
0.027
gMVP
0.47

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776330059; hg19: chr8-133036913; COSMIC: COSV99225506; API