14-49634055-CGCGGCG-CGCG

Variant names:

• chr14-49634055-CGCG-C
• rs745419780
• NM_018139.3:c.1092_1094delCGC

Variant summary

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

The NM_018139.3(DNAAF2):​c.1092_1094delCGC​(p.Ala365del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,368,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.523

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 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	c.1092_1094delCGC	p.Ala365del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.1092_1094delCGC	p.Ala365del	disruptive_inframe_deletion	Exon 1 of 2		NP_001077377.1
DNAAF2	NM_001378453.1	c.-780_-778delCGC		upstream_gene_variant			NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.1092_1094delCGC	p.Ala365del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043.3	c.1092_1094delCGC	p.Ala365del	disruptive_inframe_deletion	Exon 1 of 2	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1368252 Hom.: 0 AF XY: 0.00000445 AC XY: 3 AN XY: 673808

Gnomad4 AFR exome AF: 0.0000653

Gnomad4 AMR exome AF: 0.0000308

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000283

Gnomad4 SAS exome AF: 0.0000265

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Jun 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1092_1094del, results in the deletion of 1 amino acid(s) of the DNAAF2 protein (p.Ala365del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 572785). This variant has not been reported in the literature in individuals affected with DNAAF2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

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: rs745419780; hg19: chr14-50100773;