rs145619075

Positions:

chr10-27935163-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_018076.5(ODAD2):c.2342G>T(p.Gly781Val) variant causes a missense change. The variant allele was found at a frequency of 0.00244 in 1,613,984 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0025 ( 8 hom. )

Consequence

ODAD2
NM_018076.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 4.95

Variant links:

Genes affected

ODAD2 (HGNC:25583): (outer dynein arm docking complex subunit 2) The protein encoded by this gene contains ten Armadillo repeat motifs (ARMs) and one HEAT repeat, and is thought to be involved in ciliary and flagellar movement. This protein has been shown to localize to the ciliary axonemes and at the ciliary base of respiratory cells. Studies indicate that mutations in this gene cause partial outer dynein arm (ODA) defects in respiratory cilia. The cilia of cells with mutations in this gene displayed either reduced ciliary beat frequency and amplitude, or, complete immotility. Some individuals with primary ciliary dyskensia (PCD) have been shown to have mutations in this gene. PCD is characterized by chronic airway disease and left/right body asymmetry defects. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ODAD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12244466).

BP6

Variant 10-27935163-C-A is Benign according to our data. Variant chr10-27935163-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221004.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}. Variant chr10-27935163-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (299/152258) while in subpopulation NFE AF= 0.00331 (225/68014). AF 95% confidence interval is 0.00295. There are 0 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD2	NM_018076.5 linkuse as main transcript	c.2342G>T	p.Gly781Val	missense_variant	16/20	ENST00000305242.10	NP_060546.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD2	ENST00000305242.10 linkuse as main transcript	c.2342G>T	p.Gly781Val	missense_variant	16/20	1	NM_018076.5	ENSP00000306410	P1	Q5T2S8-1

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

299

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00331

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00209

AC:

525

AN:

251164

Hom.:

AF XY:

0.00219

AC XY:

297

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000882

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00335

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00249

AC:

3640

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

1805

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00289

Gnomad4 OTH exome

AF:

0.00227

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152258

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

121

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00331

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00253

Hom.:

Bravo

AF:

0.00207

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00199

AC:

242

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2021

- -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary ciliary dyskinesia 23

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

ODAD2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.036

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.34

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.85

MVP

0.85

MPC

0.63

ClinPred

0.057

GERP RS

5.9

Varity_R

0.78

gMVP

0.69

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over