10-27971222-A-G

Variant names:

• chr10-27971222-A-G
• rs4405206
• NM_018076.5:c.1028T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018076.5(ODAD2):​c.1028T>C​(p.Ile343Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0687 in 1,613,718 control chromosomes in the GnomAD database, including 5,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I343I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.078 (622 hom., cov: 32)
  • Exomes 𝑓: 0.068 (4429 hom.)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.436
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005333036).
• BP6: Variant 10-27971222-A-G is Benign according to our data. Variant chr10-27971222-A-G is described in ClinVar as Benign. ClinVar VariationId is 402396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

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.1028T>C	p.Ile343Thr	missense	Exon 8 of 20	NP_060546.2
	ODAD2	NM_001290020.2		c.1028T>C	p.Ile343Thr	missense	Exon 8 of 20	NP_001276949.1	A0A140VKF7
	ODAD2	NM_001312689.2		c.104T>C	p.Ile35Thr	missense	Exon 3 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.1028T>C	p.Ile343Thr	missense	Exon 8 of 20	ENSP00000306410.5	Q5T2S8-1
	ODAD2	ENST00000673439.1		c.1028T>C	p.Ile343Thr	missense	Exon 8 of 20	ENSP00000500782.1	Q5T2S8-1
	ODAD2	ENST00000852623.1		c.1028T>C	p.Ile343Thr	missense	Exon 8 of 20	ENSP00000522682.1

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11787 AN: 152008 Hom.: 620 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0879

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0969

GnomAD2 exomes AF: 0.0856 AC: 21502 AN: 251140 AF XY: 0.0863

Gnomad AFR exome AF: 0.0834

Gnomad AMR exome AF: 0.0609

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.288

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0602

Gnomad OTH exome AF: 0.0782

GnomAD4 exome AF: 0.0678 AC: 99052 AN: 1461592 Hom.: 4429 Cov.: 31 AF XY: 0.0694 AC XY: 50447 AN XY: 727078

African (AFR) AF: 0.0844 AC: 2825 AN: 33462

American (AMR) AF: 0.0637 AC: 2848 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 3009 AN: 26128

East Asian (EAS) AF: 0.252 AC: 9985 AN: 39686

South Asian (SAS) AF: 0.118 AC: 10176 AN: 86228

European-Finnish (FIN) AF: 0.0259 AC: 1382 AN: 53410

Middle Eastern (MID) AF: 0.0905 AC: 522 AN: 5768

European-Non Finnish (NFE) AF: 0.0571 AC: 63524 AN: 1111822

Other (OTH) AF: 0.0792 AC: 4781 AN: 60390

GnomAD4 genome AF: 0.0776 AC: 11805 AN: 152126 Hom.: 622 Cov.: 32 AF XY: 0.0801 AC XY: 5959 AN XY: 74380

African (AFR) AF: 0.0838 AC: 3479 AN: 41492

American (AMR) AF: 0.0882 AC: 1348 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3470

East Asian (EAS) AF: 0.267 AC: 1378 AN: 5164

South Asian (SAS) AF: 0.127 AC: 612 AN: 4820

European-Finnish (FIN) AF: 0.0277 AC: 293 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0578 AC: 3928 AN: 67990

Other (OTH) AF: 0.0988 AC: 209 AN: 2116

Alfa AF: 0.0658 Hom.: 811

Bravo AF: 0.0824

TwinsUK AF: 0.0591 AC: 219

ALSPAC AF: 0.0625 AC: 241

ESP6500AA AF: 0.0881 AC: 388

ESP6500EA AF: 0.0649 AC: 558

ExAC AF: 0.0862 AC: 10460

Asia WGS AF: 0.166 AC: 576 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Primary ciliary dyskinesia 23 (2)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.076
DANN	Benign	0.48
DEOGEN2	Benign	0.00086	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.44
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.013
Sift	Benign	0.40	T
Sift4G	Benign	0.40	T
Polyphen		0.017	B
Vest4		0.0050
MPC		0.23
ClinPred		0.0041	T
GERP RS		-8.1
Varity_R		0.052
gMVP		0.18
Mutation Taster		=97/3	polymorphism (auto)

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: rs4405206; hg19: chr10-28260151; COSMIC: COSV53463391;