rs146727740

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_023036.6(DNAI2):c.1663A>G(p.Ile555Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I555I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

DNAI2
NM_023036.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.70

Publications

0 publications found

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]

DNAI2 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAI2 links:

ENSG00000309634 (HGNC:):

ENSG00000309634 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011448592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI2	NM_023036.6 link	c.1663A>G	p.Ile555Val	missense_variant	Exon 12 of 14	ENST00000311014.11	NP_075462.3	Q9GZS0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11 link	c.1663A>G	p.Ile555Val	missense_variant	Exon 12 of 14	1	NM_023036.6	ENSP00000308312.6		Q9GZS0-1

Frequencies

GnomAD3 genomes

AF:

0.0000725

AC:

AN:

151710

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000149

AC:

AN:

248544

AF XY:

0.000238

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461316

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00130

AC:

112

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53196

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111878

Other (OTH)

AF:

0.0000828

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000725

AC:

AN:

151826

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00229

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Oct 28, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 555 of the DNAI2 protein (p.Ile555Val). This variant is present in population databases (rs146727740, gnomAD 0.1%). 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: 454935). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNAI2 protein function with a negative predictive value of 80%. 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. -

Primary ciliary dyskinesia 9

Uncertain:1

Nov 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0050

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0072

.;T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.50

T;.;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.84

.;L;L;.

PhyloP100

-1.7

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.020

.;N;N;.

REVEL

Benign

0.15

Sift

Benign

0.72

.;T;T;.

Sift4G

Benign

0.85

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.027

MVP

0.25

MPC

0.20

ClinPred

0.017

GERP RS

-8.5

Varity_R

0.024

gMVP

0.33

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over