chr17-74309359-G-C
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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):āc.1318G>Cā(p.Glu440Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000092 ( 0 hom., cov: 30)
Exomes š: 0.0000082 ( 0 hom. )
Consequence
DNAI2
NM_023036.6 missense
NM_023036.6 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 6.02
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 (MetaRNN=0.045513302).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAI2 | NM_023036.6 | c.1318G>C | p.Glu440Gln | missense_variant | 10/14 | ENST00000311014.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAI2 | ENST00000311014.11 | c.1318G>C | p.Glu440Gln | missense_variant | 10/14 | 1 | NM_023036.6 | P2 | |
ENST00000585167.1 | n.432C>G | non_coding_transcript_exon_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152160Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251382Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135882
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727226
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GnomAD4 genome AF: 0.0000919 AC: 14AN: 152278Hom.: 0 Cov.: 30 AF XY: 0.0000672 AC XY: 5AN XY: 74458
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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 | Ambry Genetics | Mar 27, 2023 | The p.E440Q variant (also known as c.1318G>C), located in coding exon 9 of the DNAI2 gene, results from a G to C substitution at nucleotide position 1318. The glutamic acid at codon 440 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 27, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 440 of the DNAI2 protein (p.Glu440Gln). This variant is present in population databases (rs182986650, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DNAI2-related conditions. ClinVar contains an entry for this variant (Variation ID: 241447). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N;.
MutationTaster
Benign
N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N;.
REVEL
Benign
Sift
Benign
.;T;T;.
Sift4G
Benign
T;T;T;T
Polyphen
0.0010
.;B;B;.
Vest4
MVP
MPC
0.23
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at