rs74050429

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018139.3(DNAAF2):c.707C>T(p.Pro236Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,559,432 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 46 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 32 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.191

Publications

5 publications found

Variant links:

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

DNAAF2 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 10
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAAF2 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=0.0028816462).

BP6

Variant 14-49634443-G-A is Benign according to our data. Variant chr14-49634443-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0134 (2036/152270) while in subpopulation AFR AF = 0.0459 (1910/41574). AF 95% confidence interval is 0.0442. There are 46 homozygotes in GnomAd4. There are 979 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 46 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF2	NM_018139.3 link	c.707C>T	p.Pro236Leu	missense_variant	Exon 1 of 3	ENST00000298292.13	NP_060609.2	Q9NVR5-1
DNAAF2	NM_001083908.2 link	c.707C>T	p.Pro236Leu	missense_variant	Exon 1 of 2		NP_001077377.1	Q9NVR5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13 link	c.707C>T	p.Pro236Leu	missense_variant	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8		Q9NVR5-1
DNAAF2	ENST00000406043.3 link	c.707C>T	p.Pro236Leu	missense_variant	Exon 1 of 2	1		ENSP00000384862.3		Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2033

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0460

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00318

AC:

551

AN:

173186

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.0472

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000268

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00152

AC:

2132

AN:

1407162

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

923

AN XY:

695738

show subpopulations

African (AFR)

AF:

0.0474

AC:

1530

AN:

32284

American (AMR)

AF:

0.00279

AC:

105

AN:

37580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24830

East Asian (EAS)

AF:

0.00

AC:

AN:

37834

South Asian (SAS)

AF:

0.000217

AC:

AN:

82962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40166

Middle Eastern (MID)

AF:

0.00677

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.000218

AC:

237

AN:

1087564

Other (OTH)

AF:

0.00350

AC:

204

AN:

58328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

137

274

411

548

685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.0134

AC:

2036

AN:

152270

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

979

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0459

AC:

1910

AN:

41574

American (AMR)

AF:

0.00470

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68002

Other (OTH)

AF:

0.0109

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

195

292

390

487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00583

Hom.:

Bravo

AF:

0.0151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0305

AC:

100

ESP6500EA

AF:

0.000135

AC:

ExAC

AF:

0.00308

AC:

357

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 10

Benign:2

Oct 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Primary ciliary dyskinesia

Benign:2

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 09, 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. -

not provided

Benign:2

Feb 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

0.19

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.024

Sift

Benign

0.054

T;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.20

B;B

Vest4

0.15

MVP

0.35

MPC

1.5

ClinPred

0.024

GERP RS

1.7

Varity_R

0.042

gMVP

0.41

Mutation Taster

=99/1

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

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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