NM_018076.5:c.2272A>G

Variant names:

• chr10-27935233-T-C
• rs143059966
• NM_018076.5:c.2272A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_018076.5(ODAD2):​c.2272A>G​(p.Ile758Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I758I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.375
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014392316).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000394 (60/152318) while in subpopulation AFR AF = 0.0012 (50/41586). AF 95% confidence interval is 0.000937. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.2272A>G	p.Ile758Val	missense	Exon 16 of 20	NP_060546.2
	ODAD2	NM_001290020.2		c.2272A>G	p.Ile758Val	missense	Exon 16 of 20	NP_001276949.1	A0A140VKF7
	ODAD2	NM_001312689.2		c.1348A>G	p.Ile450Val	missense	Exon 11 of 15	NP_001299618.1	A0A5F9ZH22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD2	ENST00000305242.10	TSL:1 MANE Select	c.2272A>G	p.Ile758Val	missense	Exon 16 of 20	ENSP00000306410.5	Q5T2S8-1
	ODAD2	ENST00000673439.1		c.2272A>G	p.Ile758Val	missense	Exon 16 of 20	ENSP00000500782.1	Q5T2S8-1
	ODAD2	ENST00000852623.1		c.2272A>G	p.Ile758Val	missense	Exon 16 of 20	ENSP00000522682.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000996 AC: 25 AN: 250988 AF XY: 0.000103

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461578 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 727074

African (AFR) AF: 0.00131 AC: 44 AN: 33466

American (AMR) AF: 0.000134 AC: 6 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111806

Other (OTH) AF: 0.000215 AC: 13 AN: 60390

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152318 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 25 AN XY: 74478

African (AFR) AF: 0.00120 AC: 50 AN: 41586

American (AMR) AF: 0.000589 AC: 9 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.000552

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)
-	1	-	Primary ciliary dyskinesia 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.33
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L
PhyloP100		0.38
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.049
Sift	Benign	0.72	T
Sift4G	Benign	0.81	T
Polyphen		0.035	B
Vest4		0.14
MVP		0.61
MPC		0.12
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.036
gMVP		0.17
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs143059966; hg19: chr10-28224162;