rs1979370

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_023036.6(DNAI2):c.1672G>A(p.Ala558Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,610,478 control chromosomes in the GnomAD database, including 631,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A558A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.78 ( 48710 hom., cov: 27)

Exomes 𝑓: 0.89 ( 582883 hom. )

Consequence

DNAI2
NM_023036.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.17

Publications

31 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.3897465E-7).

BP6

Variant 17-74312180-G-A is Benign according to our data. Variant chr17-74312180-G-A is described in ClinVar as Benign. ClinVar VariationId is 163171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI2	NM_023036.6 link	c.1672G>A	p.Ala558Thr	missense_variant	Exon 12 of 14	ENST00000311014.11	NP_075462.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11 link	c.1672G>A	p.Ala558Thr	missense_variant	Exon 12 of 14	1	NM_023036.6	ENSP00000308312.6

Frequencies

GnomAD3 genomes

AF:

0.782

AC:

118272

AN:

151280

Hom.:

48707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.491

Gnomad AMI

AF:

0.881

Gnomad AMR

AF:

0.883

Gnomad ASJ

AF:

0.889

Gnomad EAS

AF:

0.842

Gnomad SAS

AF:

0.826

Gnomad FIN

AF:

0.879

Gnomad MID

AF:

0.823

Gnomad NFE

AF:

0.905

Gnomad OTH

AF:

0.799

GnomAD2 exomes

AF:

0.864

AC:

213610

AN:

247294

AF XY:

0.868

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.933

Gnomad ASJ exome

AF:

0.881

Gnomad EAS exome

AF:

0.848

Gnomad FIN exome

AF:

0.886

Gnomad NFE exome

AF:

0.903

Gnomad OTH exome

AF:

0.878

GnomAD4 exome

AF:

0.892

AC:

1300812

AN:

1459080

Hom.:

582883

Cov.:

AF XY:

0.891

AC XY:

646683

AN XY:

725786

show subpopulations

African (AFR)

AF:

0.481

AC:

15780

AN:

32812

American (AMR)

AF:

0.927

AC:

41353

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.884

AC:

23070

AN:

26098

East Asian (EAS)

AF:

0.850

AC:

33532

AN:

39456

South Asian (SAS)

AF:

0.832

AC:

71679

AN:

86102

European-Finnish (FIN)

AF:

0.891

AC:

47248

AN:

53006

Middle Eastern (MID)

AF:

0.853

AC:

4839

AN:

5672

European-Non Finnish (NFE)

AF:

0.910

AC:

1011379

AN:

1111156

Other (OTH)

AF:

0.863

AC:

51932

AN:

60190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

8081

16162

24244

32325

40406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21404

42808

64212

85616

107020

<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:

0.781

AC:

118299

AN:

151398

Hom.:

48710

Cov.:

AF XY:

0.784

AC XY:

57965

AN XY:

73930

show subpopulations

African (AFR)

AF:

0.490

AC:

20165

AN:

41148

American (AMR)

AF:

0.883

AC:

13432

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.889

AC:

3083

AN:

3466

East Asian (EAS)

AF:

0.842

AC:

4260

AN:

5062

South Asian (SAS)

AF:

0.826

AC:

3951

AN:

4782

European-Finnish (FIN)

AF:

0.879

AC:

9236

AN:

10504

Middle Eastern (MID)

AF:

0.816

AC:

240

AN:

294

European-Non Finnish (NFE)

AF:

0.905

AC:

61460

AN:

67934

Other (OTH)

AF:

0.798

AC:

1670

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1023

2047

3070

4094

5117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.866

Hom.:

234996

Bravo

AF:

0.769

TwinsUK

AF:

0.912

AC:

3381

ALSPAC

AF:

0.919

AC:

3543

ESP6500AA

AF:

0.497

AC:

2189

ESP6500EA

AF:

0.910

AC:

7829

ExAC

AF:

0.852

AC:

103350

Asia WGS

AF:

0.808

AC:

2808

AN:

3478

EpiCase

AF:

0.902

EpiControl

AF:

0.904

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 20, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala558Thr in exon 12 of DNAI2: This variant is not expected to have clinical sig nificance because it has been identified in 49.7% (2189/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1979370).

Primary ciliary dyskinesia 9

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary ciliary dyskinesia

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 01, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0040

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0

.;T;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.27

T;.;T;T

MetaRNN

Benign

6.4e-7

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N;.

PhyloP100

-2.2

PrimateAI

Benign

0.25

PROVEAN

Benign

0.0

.;N;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;T;.

Sift4G

Benign

0.60

T;T;T;T

Vest4

0.050

ClinPred

0.027

GERP RS

-9.4

Varity_R

0.027

gMVP

0.36

Mutation Taster

=19/81

disease causing

(source)

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

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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