chr17-74309359-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_023036.6(DNAI2):ā€‹c.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

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.02
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 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
DNAI2NM_023036.6 linkuse as main transcriptc.1318G>C p.Glu440Gln missense_variant 10/14 ENST00000311014.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAI2ENST00000311014.11 linkuse as main transcriptc.1318G>C p.Glu440Gln missense_variant 10/141 NM_023036.6 P2Q9GZS0-1
ENST00000585167.1 linkuse as main transcriptn.432C>G non_coding_transcript_exon_variant 1/23

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152160
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251382
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461866
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152278
Hom.:
0
Cov.:
30
AF XY:
0.0000672
AC XY:
5
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
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:
0.0000565
Hom.:
0
Bravo
AF:
0.0000869
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingAmbry GeneticsMar 27, 2023The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2022This 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 providedclinical testingNatera, Inc.Oct 28, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
20
DANN
Benign
0.86
DEOGEN2
Benign
0.0046
.;T;T;T
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.41
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.88
D;.;D;D
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.046
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.55
N;N;N;.
MutationTaster
Benign
0.97
N;N;N;N;N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
0.20
.;N;N;.
REVEL
Benign
0.082
Sift
Benign
0.44
.;T;T;.
Sift4G
Benign
0.32
T;T;T;T
Polyphen
0.0010
.;B;B;.
Vest4
0.28
MVP
0.13
MPC
0.23
ClinPred
0.016
T
GERP RS
4.5
Varity_R
0.10
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs182986650; hg19: chr17-72305498; API