10-27860667-G-T

Variant names:

• chr10-27860667-G-T
• rs74555138
• NM_018076.5:c.2979C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018076.5(ODAD2):​c.2979C>A​(p.Asp993Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D993D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.255
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2979C>A	p.Asp993Glu	missense	Exon 19 of 20	NP_060546.2
	ODAD2	NM_001290020.2		c.2979C>A	p.Asp993Glu	missense	Exon 19 of 20	NP_001276949.1	A0A140VKF7
	ODAD2	NM_001312689.2		c.2055C>A	p.Asp685Glu	missense	Exon 14 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.2979C>A	p.Asp993Glu	missense	Exon 19 of 20	ENSP00000306410.5	Q5T2S8-1
	ODAD2	ENST00000673439.1		c.2979C>A	p.Asp993Glu	missense	Exon 19 of 20	ENSP00000500782.1	Q5T2S8-1
	ODAD2	ENST00000852623.1		c.2979C>A	p.Asp993Glu	missense	Exon 19 of 20	ENSP00000522682.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	6.4
DANN	Benign	0.97
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.26
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.58
Sift	Benign	0.10	T
Sift4G	Benign	0.12	T
Polyphen		0.92	P
Vest4		0.42
MutPred		0.54		Gain of loop (P = 0.1069)
MVP		0.65
MPC		0.54
ClinPred		0.97	D
GERP RS		-8.3
PromoterAI		-0.017	Neutral
Varity_R		0.23
gMVP		0.31
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs74555138; hg19: chr10-28149596;