17-74287103-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_023036.6(DNAI2):c.467+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
DNAI2
NM_023036.6 splice_donor_5th_base, intron
NM_023036.6 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.0002637
2
Clinical Significance
Conservation
PhyloP100: 0.0200
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]
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ACMG classification
Classification made for transcript
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 (BayesDel_noAF=-0.8).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| DNAI2 | NM_023036.6 | c.467+5C>T | splice_donor_5th_base_variant, intron_variant | ENST00000311014.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DNAI2 | ENST00000311014.11 | c.467+5C>T | splice_donor_5th_base_variant, intron_variant | 1 | NM_023036.6 | P2 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250500Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135402
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461330Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726954
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GnomAD4 genome 0.0000131 AC: 2AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74480
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 04, 2016 | This sequence change falls in intron 4 of the DNAI2 gene. It does not directly change the encoded amino acid sequence of the DNAI2 protein. This variant is present in population databases (rs529401265, ExAC 0.002%) but has not been reported in the literature in individuals with a DNAI2-related disease. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2014 | The c.467+5C>T intronic variant results from a C to T substitution 5 nucleotides after coding exon 3 in the DNAI2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is not well conserved in available vertebrate species on limited alignment. In addition, T is the reference nucleotide in four species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at