chr14-49634055-C-CGCG

Variant names:

• chr14-49634055-C-CGCG
• rs745419780
• NM_018139.3:c.1092_1094dupCGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_018139.3(DNAAF2):​c.1092_1094dupCGC​(p.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 0.00000292 in 1,368,382 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.515
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_018139.3

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	NM_018139.3	MANE Select	c.1092_1094dupCGC	p.Ala365dup	disruptive_inframe_insertion	Exon 1 of 3	NP_060609.2
	DNAAF2	NM_001083908.2		c.1092_1094dupCGC	p.Ala365dup	disruptive_inframe_insertion	Exon 1 of 2	NP_001077377.1
	DNAAF2	NM_001378453.1		c.-780_-778dupCGC		upstream_gene	N/A	NP_001365382.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	ENST00000298292.13	TSL:1 MANE Select	c.1092_1094dupCGC	p.Ala365dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000298292.8
	DNAAF2	ENST00000406043.3	TSL:1	c.1092_1094dupCGC	p.Ala365dup	disruptive_inframe_insertion	Exon 1 of 2	ENSP00000384862.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000175 AC: 2 AN: 114152 AF XY: 0.0000321

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000292 AC: 4 AN: 1368382 Hom.: 0 Cov.: 88 AF XY: 0.00000594 AC XY: 4 AN XY: 673886

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000326 AC: 1 AN: 30642

American (AMR) AF: 0.00 AC: 0 AN: 32446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23522

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35320

South Asian (SAS) AF: 0.00 AC: 0 AN: 75454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4254

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1070070

Other (OTH) AF: 0.00 AC: 0 AN: 56870

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000222786), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000436 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745419780; hg19: chr14-50100773;