14-49633744-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018139.3(DNAAF2):c.1406G>A(p.Cys469Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,593,408 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C469S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0049 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0063 ( 87 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.309

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032324195).

BP6

Variant 14-49633744-C-T is Benign according to our data. Variant chr14-49633744-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 219711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00494 (752/152336) while in subpopulation SAS AF= 0.0296 (143/4828). AF 95% confidence interval is 0.0257. There are 7 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF2	NM_018139.3 link	c.1406G>A	p.Cys469Tyr	missense_variant	Exon 1 of 3	ENST00000298292.13	NP_060609.2	Q9NVR5-1
DNAAF2	NM_001083908.2 link	c.1406G>A	p.Cys469Tyr	missense_variant	Exon 1 of 2		NP_001077377.1	Q9NVR5-2
DNAAF2	NM_001378453.1 link	c.-466G>A		5_prime_UTR_variant	Exon 1 of 2		NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13 link	c.1406G>A	p.Cys469Tyr	missense_variant	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8		Q9NVR5-1
DNAAF2	ENST00000406043.3 link	c.1406G>A	p.Cys469Tyr	missense_variant	Exon 1 of 2	1		ENSP00000384862.3		Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.00495

AC:

754

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0298

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00773

AC:

1796

AN:

232332

Hom.:

AF XY:

0.00886

AC XY:

1126

AN XY:

127084

show subpopulations

Gnomad AFR exome

AF:

0.000864

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.0000565

Gnomad SAS exome

AF:

0.0262

Gnomad FIN exome

AF:

0.00953

Gnomad NFE exome

AF:

0.00625

Gnomad OTH exome

AF:

0.00589

GnomAD4 exome

AF:

0.00629

AC:

9060

AN:

1441072

Hom.:

Cov.:

AF XY:

0.00696

AC XY:

4978

AN XY:

715636

show subpopulations

Gnomad4 AFR exome

AF:

0.000546

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.00980

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.0260

Gnomad4 FIN exome

AF:

0.00768

Gnomad4 NFE exome

AF:

0.00516

Gnomad4 OTH exome

AF:

0.00647

GnomAD4 genome

AF:

0.00494

AC:

752

AN:

152336

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

397

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000769

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0296

Gnomad4 FIN

AF:

0.0108

Gnomad4 NFE

AF:

0.00559

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00583

Hom.:

Bravo

AF:

0.00379

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000469

AC:

ESP6500EA

AF:

0.00694

AC:

ExAC

AF:

0.00801

AC:

970

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 13, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2015

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. -

Primary ciliary dyskinesia 10

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.3

DANN

Benign

0.79

DEOGEN2

Benign

0.0022

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.40

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.050

Sift

Benign

0.67

T;T

Sift4G

Benign

0.086

T;T

Polyphen

0.0

B;B

Vest4

0.097

MVP

0.092

MPC

0.86

ClinPred

0.0036

GERP RS

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.052

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over