NM_018139.3:c.186G>C

Variant names:

• chr14-49634964-C-G
• rs2985684
• NM_018139.3:c.186G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. E62E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.65 (34145 hom., cov: 36)
  • Exomes 𝑓: 0.72 (377797 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.11
• Publications: 35 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 95893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018139.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	NM_018139.3	MANE Select	c.186G>C	p.Glu62Asp	missense	Exon 1 of 3	NP_060609.2
	DNAAF2	NM_001083908.2		c.186G>C	p.Glu62Asp	missense	Exon 1 of 2	NP_001077377.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	ENST00000298292.13	TSL:1 MANE Select	c.186G>C	p.Glu62Asp	missense	Exon 1 of 3	ENSP00000298292.8
	DNAAF2	ENST00000406043.3	TSL:1	c.186G>C	p.Glu62Asp	missense	Exon 1 of 2	ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.651 AC: 99022 AN: 152152 Hom.: 34132 Cov.: 36

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

GnomAD2 exomes AF: 0.641 AC: 105022 AN: 163802 AF XY: 0.640

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 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

African (AFR) AF: 0.484 AC: 15500 AN: 32038

American (AMR) AF: 0.617 AC: 22895 AN: 37100

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 18185 AN: 25292

East Asian (EAS) AF: 0.118 AC: 4297 AN: 36424

South Asian (SAS) AF: 0.546 AC: 43811 AN: 80188

European-Finnish (FIN) AF: 0.775 AC: 37645 AN: 48572

Middle Eastern (MID) AF: 0.652 AC: 3726 AN: 5714

European-Non Finnish (NFE) AF: 0.766 AC: 830841 AN: 1084492

Other (OTH) AF: 0.677 AC: 39470 AN: 58318

GnomAD4 genome AF: 0.651 AC: 99088 AN: 152270 Hom.: 34145 Cov.: 36 AF XY: 0.648 AC XY: 48277 AN XY: 74446

African (AFR) AF: 0.496 AC: 20617 AN: 41554

American (AMR) AF: 0.661 AC: 10121 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2472 AN: 3472

East Asian (EAS) AF: 0.147 AC: 763 AN: 5182

South Asian (SAS) AF: 0.532 AC: 2568 AN: 4828

European-Finnish (FIN) AF: 0.795 AC: 8440 AN: 10618

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51722 AN: 67990

Other (OTH) AF: 0.672 AC: 1423 AN: 2116

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

Submissions by phenotype

not specified Benign:3

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

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).

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

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

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.075
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.077
Sift	Benign	0.087	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.44	B
Vest4		0.18
MutPred		0.33		Gain of catalytic residue at E66 (P = 0.0107)
MPC		1.4
ClinPred		0.079	T
GERP RS		4.2
PromoterAI		-0.0068	Neutral
Varity_R		0.12
gMVP		0.70
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2985684; hg19: chr14-50101682; COSMIC: COSV53568826;