14-49634964-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018139.3(DNAAF2):c.186G>C(p.Glu62Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,560,408 control chromosomes in the GnomAD database, including 411,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 34145 hom., cov: 36)

Exomes 𝑓: 0.72 ( 377797 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.11

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=2.1276762E-6).

BP6

Variant 14-49634964-C-G is Benign according to our data. Variant chr14-49634964-C-G is described in ClinVar as [Benign]. Clinvar id is 95893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-49634964-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF2	NM_018139.3 link	c.186G>C	p.Glu62Asp	missense_variant	Exon 1 of 3	ENST00000298292.13	NP_060609.2	Q9NVR5-1
DNAAF2	NM_001083908.2 link	c.186G>C	p.Glu62Asp	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.186G>C	p.Glu62Asp	missense_variant	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8		Q9NVR5-1
DNAAF2	ENST00000406043.3 link	c.186G>C	p.Glu62Asp	missense_variant	Exon 1 of 2	1		ENSP00000384862.3		Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.651

AC:

99022

AN:

152152

Hom.:

34132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.496

Gnomad AMI

AF:

0.828

Gnomad AMR

AF:

0.661

Gnomad ASJ

AF:

0.712

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.533

Gnomad FIN

AF:

0.795

Gnomad MID

AF:

0.690

Gnomad NFE

AF:

0.761

Gnomad OTH

AF:

0.673

GnomAD3 exomes

AF:

0.641

AC:

105022

AN:

163802

Hom.:

36042

AF XY:

0.640

AC XY:

56890

AN XY:

88932

show subpopulations

Gnomad AFR exome

AF:

0.480

Gnomad AMR exome

AF:

0.607

Gnomad ASJ exome

AF:

0.713

Gnomad EAS exome

AF:

0.147

Gnomad SAS exome

AF:

0.546

Gnomad FIN exome

AF:

0.779

Gnomad NFE exome

AF:

0.757

Gnomad OTH exome

AF:

0.681

GnomAD4 exome

AF:

0.722

AC:

1016370

AN:

1408138

Hom.:

377797

Cov.:

111

AF XY:

0.717

AC XY:

499101

AN XY:

695730

show subpopulations

Gnomad4 AFR exome

AF:

0.484

Gnomad4 AMR exome

AF:

0.617

Gnomad4 ASJ exome

AF:

0.719

Gnomad4 EAS exome

AF:

0.118

Gnomad4 SAS exome

AF:

0.546

Gnomad4 FIN exome

AF:

0.775

Gnomad4 NFE exome

AF:

0.766

Gnomad4 OTH exome

AF:

0.677

GnomAD4 genome

AF:

0.651

AC:

99088

AN:

152270

Hom.:

34145

Cov.:

AF XY:

0.648

AC XY:

48277

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.496

Gnomad4 AMR

AF:

0.661

Gnomad4 ASJ

AF:

0.712

Gnomad4 EAS

AF:

0.147

Gnomad4 SAS

AF:

0.532

Gnomad4 FIN

AF:

0.795

Gnomad4 NFE

AF:

0.761

Gnomad4 OTH

AF:

0.672

Alfa

AF:

0.717

Hom.:

10431

Bravo

AF:

0.633

TwinsUK

AF:

0.781

AC:

2897

ALSPAC

AF:

0.769

AC:

2962

ESP6500AA

AF:

0.574

AC:

2117

ESP6500EA

AF:

0.779

AC:

6094

ExAC

AF:

0.573

AC:

61715

Asia WGS

AF:

0.394

AC:

1368

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu62Asp in exon 1 of DNAAF2: This variant is not expected to have clinical sign ificance because it has been identified in 42.6% (1571/3688) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs2985684). -

Jul 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 10

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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. -

Sep 21, 2015

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

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

- -

Nov 26, 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

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

Uncertain

0.42

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.075

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0000021

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.077

Sift

Benign

0.087

T;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.44

B;P

Vest4

0.18

MutPred

0.33

Gain of catalytic residue at E66 (P = 0.0107);Gain of catalytic residue at E66 (P = 0.0107);

MPC

1.4

ClinPred

0.079

GERP RS

4.2

Varity_R

0.12

gMVP

0.70

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