14-49625753-T-C

Variant names:

• chr14-49625753-T-C
• rs9989177
• NM_018139.3:c.2303A>G

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.2303A>G​(p.Asp768Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,611,812 control chromosomes in the GnomAD database, including 208,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14938 hom., cov: 32)
  • Exomes 𝑓: 0.50 (193523 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.44
• Publications: 44 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=6.0439936E-5).
• BP6: Variant 14-49625753-T-C is Benign according to our data. Variant chr14-49625753-T-C is described in ClinVar as Benign. ClinVar VariationId is 163091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 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.2303A>G	p.Asp768Gly	missense	Exon 3 of 3	NP_060609.2
	DNAAF2	NM_001083908.2		c.2159A>G	p.Asp720Gly	missense	Exon 2 of 2	NP_001077377.1
	DNAAF2	NM_001378453.1		c.92A>G	p.Asp31Gly	missense	Exon 2 of 2	NP_001365382.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	ENST00000298292.13	TSL:1 MANE Select	c.2303A>G	p.Asp768Gly	missense	Exon 3 of 3	ENSP00000298292.8
	DNAAF2	ENST00000406043.3	TSL:1	c.2159A>G	p.Asp720Gly	missense	Exon 2 of 2	ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62300 AN: 152002 Hom.: 14933 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.424

GnomAD2 exomes AF: 0.445 AC: 110924 AN: 249242 AF XY: 0.459

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.267

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.483

GnomAD4 exome AF: 0.505 AC: 737044 AN: 1459690 Hom.: 193523 Cov.: 45 AF XY: 0.506 AC XY: 367573 AN XY: 726018

African (AFR) AF: 0.179 AC: 5966 AN: 33346

American (AMR) AF: 0.279 AC: 12402 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 14988 AN: 26096

East Asian (EAS) AF: 0.0987 AC: 3907 AN: 39590

South Asian (SAS) AF: 0.482 AC: 41277 AN: 85606

European-Finnish (FIN) AF: 0.568 AC: 30309 AN: 53318

Middle Eastern (MID) AF: 0.478 AC: 2750 AN: 5758

European-Non Finnish (NFE) AF: 0.537 AC: 596838 AN: 1111216

Other (OTH) AF: 0.474 AC: 28607 AN: 60296

GnomAD4 genome AF: 0.410 AC: 62327 AN: 152122 Hom.: 14938 Cov.: 32 AF XY: 0.411 AC XY: 30544 AN XY: 74370

African (AFR) AF: 0.187 AC: 7750 AN: 41532

American (AMR) AF: 0.351 AC: 5361 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1958 AN: 3468

East Asian (EAS) AF: 0.126 AC: 653 AN: 5192

South Asian (SAS) AF: 0.477 AC: 2303 AN: 4824

European-Finnish (FIN) AF: 0.585 AC: 6179 AN: 10564

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36546 AN: 67956

Other (OTH) AF: 0.427 AC: 902 AN: 2114

Alfa AF: 0.492 Hom.: 75765

Bravo AF: 0.377

TwinsUK AF: 0.546 AC: 2023

ALSPAC AF: 0.544 AC: 2098

ESP6500AA AF: 0.193 AC: 852

ESP6500EA AF: 0.537 AC: 4620

ExAC AF: 0.451 AC: 54694

Asia WGS AF: 0.318 AC: 1103 AN: 3478

EpiCase AF: 0.530

EpiControl AF: 0.539

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 10 Benign:3

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 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:3

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asp768Gly in exon 3 of DNAAF2: This variant is not expected to have clinical sig nificance because it has been identified in 46.3% (3980/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs9989177).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Congenital disorder of glycosylation Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.000060	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.4
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.089
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.037	D
Polyphen		0.65	P
Vest4		0.019
MPC		1.0
ClinPred		0.021	T
GERP RS		5.7
Varity_R		0.12
gMVP		0.22
Mutation Taster		=98/2	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: rs9989177; hg19: chr14-50092471; COSMIC: COSV53568217; COSMIC: COSV53568217;