Genetic Variant DNAAF2:p.Ala364_Ala365dup (chr14-49634055-C-CGCGGCG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018139.3(DNAAF2):c.1089_1094dupCGCCGC(p.Ala364_Ala365dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,520,554 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

DNAAF2
NM_018139.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.515

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF2	NM_018139.3 link	c.1089_1094dupCGCCGC	p.Ala364_Ala365dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000298292.13	NP_060609.2	Q9NVR5-1
DNAAF2	NM_001083908.2 link	c.1089_1094dupCGCCGC	p.Ala364_Ala365dup	disruptive_inframe_insertion	Exon 1 of 2		NP_001077377.1	Q9NVR5-2
DNAAF2	NM_001378453.1 link	c.-783_-778dupCGCCGC		upstream_gene_variant			NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13 link	c.1089_1094dupCGCCGC	p.Ala364_Ala365dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8		Q9NVR5-1
DNAAF2	ENST00000406043.3 link	c.1089_1094dupCGCCGC	p.Ala364_Ala365dup	disruptive_inframe_insertion	Exon 1 of 2	1		ENSP00000384862.3		Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.0000161

AC:

AN:

1368380

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

673886

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000308

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000187

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Jan 10, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel in-frame duplication with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a DNAAF2-related disease. This sequence change inserts 6 nucleotides in exon 1 of the DNAAF2 mRNA (c.1089_1094dupCGCCGC). This leads to the insertion of 2 amino acid residues in the DNAAF2 protein (p.Ala364_Ala365dup) but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

14-49634055-CGCGGCG-CGCGGCGGCGGCG

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