rs752924362

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_023036.6(DNAI2):​c.1304G>A​(p.Trp435*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

DNAI2
NM_023036.6 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.79
Variant links:
Genes affected
DNAI2 (HGNC:18744): (dynein axonemal intermediate chain 2) The protein encoded by this gene belongs to the dynein intermediate chain family, and is part of the dynein complex of respiratory cilia and sperm flagella. Mutations in this gene are associated with primary ciliary dyskinesia type 9. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-74309345-G-A is Pathogenic according to our data. Variant chr17-74309345-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAI2NM_023036.6 linkc.1304G>A p.Trp435* stop_gained Exon 10 of 14 ENST00000311014.11 NP_075462.3 Q9GZS0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAI2ENST00000311014.11 linkc.1304G>A p.Trp435* stop_gained Exon 10 of 14 1 NM_023036.6 ENSP00000308312.6 Q9GZS0-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152160
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00317
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000159
AC:
40
AN:
251390
Hom.:
0
AF XY:
0.000184
AC XY:
25
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00337
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000657
AC:
96
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.0000633
AC XY:
46
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00272
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152160
Hom.:
0
Cov.:
30
AF XY:
0.0000673
AC XY:
5
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00317
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000290
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 9 Pathogenic:5
Jun 07, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 04, 2018
Illumina Laboratory Services, Illumina
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The DNAI2 c.1304G>A (p.Trp435Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp435Ter variant has been reported in one study and found in three individuals with primary ciliary dyskinesia, all in a homozygous state (Knowles et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.003376 in the Ashkenazi Jewish population of the Genome Aggregation Database. It is suggested that this variant may be a founder variant in the Ashkenazi Jewish population (Knowles et al. 2013; Fedick et al. 2015). Based on the potential impact of stop-gained variants and the clinical evidence, the p.Trp435Ter variant is classified as likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 10, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Feb 09, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 18, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary ciliary dyskinesia Pathogenic:4
Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 03, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Trp435X variant in DNAI2 has been reported in 3 Ashkenazi Jewish individua ls with PCD, all of whom were homozygous for the variant, and in 2 Caucasian sib lings with PCD, both of whom were compound heterozygous with a second pathogenic DNAI2 variant (Knowles 2013, Zariwala 2013). This variant has been identified i n 14/66582 European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs752924362). Please note that presence in the general population does not contradict pathogenicity, especially for recessive d isorders and disorders with reduced penetrance. This nonsense variant leads to a premature termination codon at position 435, which is predicted to lead to a tr uncated or absent protein. In summary, this variant meets our criteria to be cla ssified as pathogenic for PCD in an autosomal recessive manner (http://www.partn ers.org/personalizedmedicine/LMM) based on multiple reports of this variant in i ndividuals with PCD and the predicted impact of the variant. -

Jan 21, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp435*) in the DNAI2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAI2 are known to be pathogenic (PMID: 18950741, 23891469). This variant is present in population databases (rs752924362, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23261302, 23891469). ClinVar contains an entry for this variant (Variation ID: 228335). For these reasons, this variant has been classified as Pathogenic. -

May 30, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.W435* pathogenic mutation (also known as c.1304G>A), located in coding exon 9 of the DNAI2 gene, results from a G to A substitution at nucleotide position 1304. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This variant was identified in several individuals in the homozygous and compound heterozygous state with a clinical diagnosis or high clinical suspicion of primary ciliary dyskinesia (Zariwala MA et al. Am J Hum Genet, 2013 Aug;93:336-45; Knowles MR et al. Am J Hum Genet, 2013 Jan;92:99-106; Shoemark A et al. Eur Respir J, 2022 Nov;60:). It was also identified in the homozygous state in an individual with bronchiectasis (Gileles-Hillel A et al. ERJ Open Res, 2020 Oct;6:). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1
Apr 20, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25802884, 23261302, 33447612, 35753512, 23891469, 31980526, 35728977) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
48
DANN
Uncertain
1.0
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.45
GERP RS
5.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752924362; hg19: chr17-72305484; API