dbSNP rs143215183: ODAD2:p.Val295Leu (chr10-27981519-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018076.5(ODAD2):c.883G>C(p.Val295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,534,874 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 5 hom. )

Consequence

ODAD2
NM_018076.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.36

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015191466).

BP6

Variant 10-27981519-C-G is Benign according to our data. Variant chr10-27981519-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241266.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0013 (198/152172) while in subpopulation NFE AF = 0.00212 (144/67992). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ODAD2	NM_018076.5	MANE Select	c.883G>C	p.Val295Leu	missense	Exon 7 of 20	NP_060546.2
ODAD2	NM_001290020.2		c.883G>C	p.Val295Leu	missense	Exon 7 of 20	NP_001276949.1	A0A140VKF7
ODAD2	NM_001312689.2		c.-42G>C		5_prime_UTR	Exon 2 of 15	NP_001299618.1	A0A5F9ZH22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ODAD2	ENST00000305242.10	TSL:1 MANE Select	c.883G>C	p.Val295Leu	missense	Exon 7 of 20	ENSP00000306410.5	Q5T2S8-1
ODAD2	ENST00000673439.1		c.883G>C	p.Val295Leu	missense	Exon 7 of 20	ENSP00000500782.1	Q5T2S8-1
ODAD2	ENST00000852623.1		c.883G>C	p.Val295Leu	missense	Exon 7 of 20	ENSP00000522682.1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00212

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00154

AC:

282

AN:

182870

AF XY:

0.00159

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000747

Gnomad ASJ exome

AF:

0.00380

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000344

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.00201

GnomAD4 exome

AF:

0.00173

AC:

2388

AN:

1382702

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

1177

AN XY:

685788

show subpopulations

African (AFR)

AF:

0.000214

AC:

AN:

27984

American (AMR)

AF:

0.00116

AC:

AN:

24084

Ashkenazi Jewish (ASJ)

AF:

0.00401

AC:

AN:

23720

East Asian (EAS)

AF:

0.00

AC:

AN:

34722

South Asian (SAS)

AF:

0.000308

AC:

AN:

71340

European-Finnish (FIN)

AF:

0.000493

AC:

AN:

52694

Middle Eastern (MID)

AF:

0.00360

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.00194

AC:

2101

AN:

1085496

Other (OTH)

AF:

0.00158

AC:

AN:

57102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

105

210

315

420

525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00130

AC:

198

AN:

152172

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41524

American (AMR)

AF:

0.00105

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00212

AC:

144

AN:

67992

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.00132

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00164

AC:

199

Asia WGS

AF:

0.000578

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Primary ciliary dyskinesia 23 (2)

ODAD2-related disorder (1)

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0055

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.74

M_CAP

Benign

0.028

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.9

PhyloP100

1.4

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Uncertain

0.011

Sift4G

Uncertain

0.019

Polyphen

0.93

Vest4

0.33

MVP

0.62

MPC

0.34

ClinPred

0.028

GERP RS

3.1

PromoterAI

0.011

Neutral

(source)

Varity_R

0.19

gMVP

0.78

Mutation Taster

=295/5

polymorphism

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over