chr10-27812526-C-A

Variant names:

• chr10-27812526-C-A
• rs3737184
• NM_018076.5:c.3121G>T

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.3121G>T​(p.Ala1041Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,612,734 control chromosomes in the GnomAD database, including 2,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1041T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (226 hom., cov: 32)
  • Exomes 𝑓: 0.020 (2416 hom.)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.41
• Publications: 11 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=0.0017198324).
• BP6: Variant 10-27812526-C-A is Benign according to our data. Variant chr10-27812526-C-A is described in ClinVar as Benign. ClinVar VariationId is 417179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 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.3121G>T	p.Ala1041Ser	missense	Exon 20 of 20	NP_060546.2
	ODAD2	NM_001290020.2		c.3121G>T	p.Ala1041Ser	missense	Exon 20 of 20	NP_001276949.1	A0A140VKF7
	ODAD2	NM_001312689.2		c.2197G>T	p.Ala733Ser	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.3121G>T	p.Ala1041Ser	missense	Exon 20 of 20	ENSP00000306410.5	Q5T2S8-1
	ODAD2	ENST00000673439.1		c.3121G>T	p.Ala1041Ser	missense	Exon 20 of 20	ENSP00000500782.1	Q5T2S8-1
	ODAD2	ENST00000852623.1		c.3121G>T	p.Ala1041Ser	missense	Exon 20 of 20	ENSP00000522682.1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3331 AN: 152062 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.0505 AC: 12610 AN: 249854 AF XY: 0.0495

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.221

Gnomad FIN exome AF: 0.0374

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.0374

GnomAD4 exome AF: 0.0199 AC: 29010 AN: 1460554 Hom.: 2416 Cov.: 30 AF XY: 0.0220 AC XY: 16017 AN XY: 726570

African (AFR) AF: 0.00203 AC: 68 AN: 33424

American (AMR) AF: 0.104 AC: 4595 AN: 44290

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26120

East Asian (EAS) AF: 0.255 AC: 10095 AN: 39626

South Asian (SAS) AF: 0.109 AC: 9330 AN: 85870

European-Finnish (FIN) AF: 0.0356 AC: 1900 AN: 53404

Middle Eastern (MID) AF: 0.00694 AC: 40 AN: 5764

European-Non Finnish (NFE) AF: 0.00114 AC: 1272 AN: 1111712

Other (OTH) AF: 0.0272 AC: 1641 AN: 60344

GnomAD4 genome AF: 0.0219 AC: 3339 AN: 152180 Hom.: 226 Cov.: 32 AF XY: 0.0262 AC XY: 1949 AN XY: 74406

African (AFR) AF: 0.00318 AC: 132 AN: 41540

American (AMR) AF: 0.0616 AC: 942 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3466

East Asian (EAS) AF: 0.215 AC: 1111 AN: 5168

South Asian (SAS) AF: 0.116 AC: 559 AN: 4808

European-Finnish (FIN) AF: 0.0383 AC: 406 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68006

Other (OTH) AF: 0.0185 AC: 39 AN: 2108

Alfa AF: 0.0135 Hom.: 385

Bravo AF: 0.0232

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.0478 AC: 5798

Asia WGS AF: 0.152 AC: 528 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.0035	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.30
Sift	Benign	0.091	T
Sift4G	Benign	0.26	T
Polyphen		0.21	B
Vest4		0.15
MPC		0.25
ClinPred		0.014	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.27
Mutation Taster		=92/8	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: rs3737184; hg19: chr10-28101455; COSMIC: COSV59459467;