NM_018076.5:c.3086C>T

Variant names:

• chr10-27812561-G-A
• rs138588942
• NM_018076.5:c.3086C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018076.5(ODAD2):​c.3086C>T​(p.Ser1029Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,613,140 control chromosomes in the GnomAD database, including 2 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 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.85
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018236786).
• BP6: Variant 10-27812561-G-A is Benign according to our data. Variant chr10-27812561-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 417175.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00107 (163/152262) while in subpopulation AFR AF = 0.00371 (154/41538). AF 95% confidence interval is 0.00323. There are 0 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD2	NM_018076.5	MANE Select	c.3086C>T	p.Ser1029Phe	missense	Exon 20 of 20	NP_060546.2
	ODAD2	NM_001290020.2		c.3086C>T	p.Ser1029Phe	missense	Exon 20 of 20	NP_001276949.1	A0A140VKF7
	ODAD2	NM_001312689.2		c.2162C>T	p.Ser721Phe	missense	Exon 15 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.3086C>T	p.Ser1029Phe	missense	Exon 20 of 20	ENSP00000306410.5	Q5T2S8-1
	ODAD2	ENST00000673439.1		c.3086C>T	p.Ser1029Phe	missense	Exon 20 of 20	ENSP00000500782.1	Q5T2S8-1
	ODAD2	ENST00000852623.1		c.3086C>T	p.Ser1029Phe	missense	Exon 20 of 20	ENSP00000522682.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000959

GnomAD2 exomes AF: 0.000272 AC: 68 AN: 250250 AF XY: 0.000207

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 193 AN: 1460878 Hom.: 2 Cov.: 30 AF XY: 0.000100 AC XY: 73 AN XY: 726716

African (AFR) AF: 0.00458 AC: 153 AN: 33428

American (AMR) AF: 0.000203 AC: 9 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111790

Other (OTH) AF: 0.000381 AC: 23 AN: 60350

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74452

African (AFR) AF: 0.00371 AC: 154 AN: 41538

American (AMR) AF: 0.000457 AC: 7 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000416 Hom.: 1

Bravo AF: 0.00120

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000346 AC: 42

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Primary ciliary dyskinesia 23 (2)
-	1	-	not provided (1)
-	-	1	ODAD2-related disorder (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.018	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.65
Sift	Benign	0.050	D
Sift4G	Uncertain	0.060	T
Polyphen		0.92	P
Vest4		0.25
MVP		0.93
MPC		0.22
ClinPred		0.067	T
GERP RS		5.7
Varity_R		0.33
gMVP		0.37
Mutation Taster		=45/55	disease causing

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: rs138588942; hg19: chr10-28101490;