10-27860841-G-T

Variant names:

• chr10-27860841-G-T
• rs35181927
• NM_018076.5:c.2805C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018076.5(ODAD2):​c.2805C>A​(p.Asn935Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,642 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (21 hom.)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0890
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047443807).
• BP6: Variant 10-27860841-G-T is Benign according to our data. Variant chr10-27860841-G-T is described in ClinVar as Benign. ClinVar VariationId is 417172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00786 (1197/152258) while in subpopulation AFR AF = 0.0274 (1138/41544). AF 95% confidence interval is 0.0261. There are 13 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR 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.2805C>A	p.Asn935Lys	missense	Exon 19 of 20	NP_060546.2
	ODAD2	NM_001290020.2		c.2805C>A	p.Asn935Lys	missense	Exon 19 of 20	NP_001276949.1
	ODAD2	NM_001312689.2		c.1881C>A	p.Asn627Lys	missense	Exon 14 of 15	NP_001299618.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD2	ENST00000305242.10	TSL:1 MANE Select	c.2805C>A	p.Asn935Lys	missense	Exon 19 of 20	ENSP00000306410.5
	ODAD2	ENST00000673439.1		c.2805C>A	p.Asn935Lys	missense	Exon 19 of 20	ENSP00000500782.1
	ODAD2	ENST00000852623.1		c.2805C>A	p.Asn935Lys	missense	Exon 19 of 20	ENSP00000522682.1

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1198 AN: 152140 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00176 AC: 442 AN: 250760 AF XY: 0.00129

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000746 AC: 1090 AN: 1461384 Hom.: 21 Cov.: 31 AF XY: 0.000644 AC XY: 468 AN XY: 727006

African (AFR) AF: 0.0268 AC: 897 AN: 33460

American (AMR) AF: 0.000939 AC: 42 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86246

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

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111598

Other (OTH) AF: 0.00194 AC: 117 AN: 60378

GnomAD4 genome AF: 0.00786 AC: 1197 AN: 152258 Hom.: 13 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74446

African (AFR) AF: 0.0274 AC: 1138 AN: 41544

American (AMR) AF: 0.00262 AC: 40 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68014

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00315 Hom.: 12

Bravo AF: 0.00893

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00231 AC: 281

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	3.1
DANN	Benign	0.95
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.089
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.017	D
Polyphen		0.072	B
Vest4		0.45
MutPred		0.23		Gain of MoRF binding (P = 0.03)
MVP		0.37
MPC		0.28
ClinPred		0.057	T
GERP RS		-9.0
PromoterAI		0.027	Neutral
Varity_R		0.26
gMVP		0.38
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35181927; hg19: chr10-28149770; COSMIC: COSV99044453;