NM_018076.5:c.383C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_018076.5(ODAD2):c.383C>T(p.Ala128Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000759 in 1,317,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A128G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ODAD2
NM_018076.5 missense, splice_region

Scores

Splicing: ADA: 0.6468

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.02

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 23
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ODAD2 links:

LOC112268060 (HGNC:):

LOC112268060 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27982807).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018076.5. 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
	ODAD2	NM_018076.5	MANE Select	c.383C>T	p.Ala128Val	missense splice_region	Exon 4 of 20	NP_060546.2
	ODAD2	NM_001290020.2		c.383C>T	p.Ala128Val	missense splice_region	Exon 4 of 20	NP_001276949.1	A0A140VKF7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ODAD2	ENST00000305242.10	TSL:1 MANE Select	c.383C>T	p.Ala128Val	missense splice_region	Exon 4 of 20	ENSP00000306410.5	Q5T2S8-1
ODAD2	ENST00000673439.1		c.383C>T	p.Ala128Val	missense splice_region	Exon 4 of 20	ENSP00000500782.1	Q5T2S8-1
ODAD2	ENST00000852623.1		c.383C>T	p.Ala128Val	missense splice_region	Exon 4 of 20	ENSP00000522682.1

Frequencies

GnomAD3 genomes

AF:

0.00000700

AC:

AN:

142870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000261

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:

0.00

GnomAD4 exome

AF:

7.59e-7

AC:

AN:

1317734

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

647934

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28104

American (AMR)

AF:

0.00

AC:

AN:

22974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21898

East Asian (EAS)

AF:

0.00

AC:

AN:

34590

South Asian (SAS)

AF:

0.00

AC:

AN:

67578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3700

European-Non Finnish (NFE)

AF:

9.56e-7

AC:

AN:

1045570

Other (OTH)

AF:

0.00

AC:

AN:

54148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000700

AC:

AN:

142870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69264

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000261

AC:

AN:

38356

American (AMR)

AF:

0.00

AC:

AN:

14218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3356

East Asian (EAS)

AF:

0.00

AC:

AN:

4294

South Asian (SAS)

AF:

0.00

AC:

AN:

4354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66192

Other (OTH)

AF:

0.00

AC:

AN:

1956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

M_CAP

Benign

0.030

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.6

PhyloP100

3.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

REVEL

Benign

0.15

Sift

Uncertain

0.020

Sift4G

Uncertain

0.034

Polyphen

0.99

Vest4

0.20

MutPred

0.29

Loss of helix (P = 0.0072)

MVP

0.76

MPC

0.55

ClinPred

0.95

GERP RS

5.0

Varity_R

0.096

gMVP

0.29

Mutation Taster

=275/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.65

dbscSNV1_RF

Benign

0.60

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over