rs572322476

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_018139.3(DNAAF2):c.58G>C(p.Val20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000733 in 1,581,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V20D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.02

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018696934).

BP6

Variant 14-49635092-C-G is Benign according to our data. Variant chr14-49635092-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261021.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000427 (65/152370) while in subpopulation AMR AF = 0.00327 (50/15308). AF 95% confidence interval is 0.00254. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF2	NM_018139.3 link	c.58G>C	p.Val20Leu	missense_variant	Exon 1 of 3	ENST00000298292.13	NP_060609.2	Q9NVR5-1
DNAAF2	NM_001083908.2 link	c.58G>C	p.Val20Leu	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.58G>C	p.Val20Leu	missense_variant	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8		Q9NVR5-1
DNAAF2	ENST00000406043.3 link	c.58G>C	p.Val20Leu	missense_variant	Exon 1 of 2	1		ENSP00000384862.3		Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.0000368

AC:

AN:

190312

AF XY:

0.0000288

show subpopulations

Gnomad AFR exome

AF:

0.000100

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000201

GnomAD4 exome

AF:

0.0000357

AC:

AN:

1429554

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

708354

show subpopulations

African (AFR)

AF:

0.0000611

AC:

AN:

32714

American (AMR)

AF:

0.000648

AC:

AN:

40124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25564

East Asian (EAS)

AF:

0.00

AC:

AN:

37778

South Asian (SAS)

AF:

0.00

AC:

AN:

81854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096920

Other (OTH)

AF:

0.000389

AC:

AN:

59122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000427

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41592

American (AMR)

AF:

0.00327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000712

Hom.:

Bravo

AF:

0.000975

ExAC

AF:

0.00000842

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Dec 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.58G>C (p.V20L) alteration is located in exon 1 (coding exon 1) of the DNAAF2 gene. This alteration results from a G to C substitution at nucleotide position 58, causing the valine (V) at amino acid position 20 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 20 of the DNAAF2 protein (p.Val20Leu). This variant is present in population databases (rs572322476, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNAAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 261021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAAF2 protein function. 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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0015

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.074

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L

PhyloP100

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.055

Sift

Benign

0.38

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.084

B;P

Vest4

0.34

MVP

0.30

MPC

1.4

ClinPred

0.079

GERP RS

4.4

PromoterAI

0.0035

Neutral

(source)

Varity_R

0.19

gMVP

0.52

Mutation Taster

=95/5

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