rs2985685

chr14-49634652-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_018139.3(DNAAF2):c.498C>T(p.Ala166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,606,680 control chromosomes in the GnomAD database, including 422,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (34105 hom., cov: 35)
  • Exomes 𝑓: 0.72 (388720 hom.)
• Consequence: DNAAF2 NM_018139.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.913

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 14-49634652-G-A is Benign according to our data. Variant chr14-49634652-G-A is described in ClinVar as [Benign]. Clinvar id is 95894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-49634652-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.913 with no splicing effect.
• 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/exons	MANE	UniProt
DNAAF2	NM_018139.3	c.498C>T	p.Ala166=	synonymous_variant	1/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.498C>T	p.Ala166=	synonymous_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.498C>T	p.Ala166=	synonymous_variant	1/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.498C>T	p.Ala166=	synonymous_variant	1/2	1		A2

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98942 AN: 152076 Hom.: 34092 Cov.: 35

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.148

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: 0.646 AC: 153188 AN: 237064 Hom.: 53024 AF XY: 0.650 AC XY: 84526 AN XY: 130064

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.603

Gnomad ASJ exome AF: 0.717

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.548

Gnomad FIN exome AF: 0.778

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.690

GnomAD4 exome AF: 0.720 AC: 1047179 AN: 1454488 Hom.: 388720 Cov.: 92 AF XY: 0.716 AC XY: 518273 AN XY: 723902

Gnomad4 AFR exome AF: 0.485

Gnomad4 AMR exome AF: 0.612

Gnomad4 ASJ exome AF: 0.720

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.774

Gnomad4 NFE exome AF: 0.766

Gnomad4 OTH exome AF: 0.679

GnomAD4 genome AF: 0.651 AC: 99006 AN: 152192 Hom.: 34105 Cov.: 35 AF XY: 0.648 AC XY: 48225 AN XY: 74418

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.712

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.532

Gnomad4 FIN AF: 0.795

Gnomad4 NFE AF: 0.761

Gnomad4 OTH AF: 0.673

Alfa AF: 0.725 Hom.: 12498

Bravo AF: 0.633

Asia WGS AF: 0.393 AC: 1367 AN: 3478

EpiCase AF: 0.755

EpiControl AF: 0.765

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala166Ala in exon 1 of DNAAF2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 47.4% (1842/3888) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2985685). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 10 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 26, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	7.7
Dann	Benign	0.91

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

Other links and lift over

dbSNP: rs2985685; hg19: chr14-50101370; COSMIC: COSV53568316; COSMIC: COSV53568316;