chr19-48297010-G-A

Position:

• chr19-48297010-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001364171.2(ODAD1):​c.2090C>T​(p.Pro697Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,609,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ODAD1 NM_001364171.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.27

Genes affected

ODAD1 (HGNC:26560): (outer dynein arm docking complex subunit 1) This gene encodes a coiled-coil domain-containing protein that is a component of the outer dynein arm docking complex in cilia cells. Mutations in this gene may cause primary ciliary dyskinesia 20. [provided by RefSeq, May 2013]

ODAD1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05217552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD1	NM_001364171.2	c.2090C>T	p.Pro697Leu	missense_variant	16/16	ENST00000674294.1	NP_001351100.1
ODAD1	NM_144577.4	c.1979C>T	p.Pro660Leu	missense_variant	14/14		NP_653178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD1	ENST00000674294.1	c.2090C>T	p.Pro697Leu	missense_variant	16/16		NM_001364171.2	ENSP00000501363.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

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

GnomAD3 exomes AF: 0.0000689 AC: 17 AN: 246844 Hom.: 0 AF XY: 0.0000523 AC XY: 7 AN XY: 133754

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000495

Gnomad NFE exome AF: 0.0000538

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1457344 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 725002

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000584

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74346

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2021	This sequence change replaces proline with leucine at codon 660 of the CCDC114 protein (p.Pro660Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs768598609, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with CCDC114-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 27, 2022	The p.P660L variant (also known as c.1979C>T), located in coding exon 13 of the CCDC114 gene, results from a C to T substitution at nucleotide position 1979. The proline at codon 660 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.072
Sift	Benign	0.28	T
Sift4G	Benign	1.0	T
Polyphen		0.059	B
Vest4		0.17
MVP		0.24
MPC		0.76
ClinPred		0.027	T
GERP RS		-1.4
Varity_R		0.028
gMVP		0.087

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

Publications

LitVar

Other links and lift over

dbSNP: rs768598609; hg19: chr19-48800267;