rs397515341

chr14-49633935-A-AGCCACGCAGGTATCGT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_018139.3(DNAAF2):c.1214_1215insACGATACCTGCGTGGC(p.Gly406ArgfsTer90) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000719 in 1,530,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A405A) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.116

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-49633935-A-AGCCACGCAGGTATCGT is Pathogenic according to our data. Variant chr14-49633935-A-AGCCACGCAGGTATCGT is described in ClinVar as [Pathogenic]. Clinvar id is 208847.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF2	NM_018139.3	c.1214_1215insACGATACCTGCGTGGC	p.Gly406ArgfsTer90	frameshift_variant	1/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.1214_1215insACGATACCTGCGTGGC	p.Gly406ArgfsTer90	frameshift_variant	1/2
DNAAF2	NM_001378453.1	c.-658_-657insACGATACCTGCGTGGC		5_prime_UTR_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.1214_1215insACGATACCTGCGTGGC	p.Gly406ArgfsTer90	frameshift_variant	1/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.1214_1215insACGATACCTGCGTGGC	p.Gly406ArgfsTer90	frameshift_variant	1/2	1		A2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151556 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000780 AC: 1 AN: 128198 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 70182

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000181

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000508 AC: 7 AN: 1379194 Hom.: 0 Cov.: 91 AF XY: 0.00000441 AC XY: 3 AN XY: 680176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000119

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151556 Hom.: 0 Cov.: 33 AF XY: 0.0000405 AC XY: 3 AN XY: 74030

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000379

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary ciliary dyskinesia 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 04, 2008

- -

Kartagener syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515341; hg19: chr14-50100653;