chr10-27983896-C-G

Variant names:

• chr10-27983896-C-G
• rs201056632
• NM_018076.5:c.766G>C

Variant summary

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

The NM_018076.5(ODAD2):​c.766G>C​(p.Asp256His) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D256N) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• Publications: 4 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC112268060 (HGNC:):

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD2	NM_018076.5	MANE Select	c.766G>C	p.Asp256His	missense	Exon 6 of 20	NP_060546.2
	ODAD2	NM_001290020.2		c.766G>C	p.Asp256His	missense	Exon 6 of 20	NP_001276949.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD2	ENST00000305242.10	TSL:1 MANE Select	c.766G>C	p.Asp256His	missense	Exon 6 of 20	ENSP00000306410.5
	ODAD2	ENST00000673439.1		c.766G>C	p.Asp256His	missense	Exon 6 of 20	ENSP00000500782.1
	ODAD2	ENST00000434029.1	TSL:2	n.448G>C		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

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

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ 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.

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.38		Loss of solvent accessibility (P = 0.0217)
MVP		0.81
MPC		0.79
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.61
gMVP		0.91
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201056632; hg19: chr10-28272825;