rs1555328130

chr14-49634917-A-AGCACATG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018139.3(DNAAF2):c.232_233insCATGTGC(p.Leu78ProfsTer118) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 35)
• Consequence: DNAAF2 NM_018139.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.192

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 12 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 14-49634917-A-AGCACATG is Pathogenic according to our data. Variant chr14-49634917-A-AGCACATG is described in ClinVar as [Pathogenic]. Clinvar id is 454904.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF2	NM_018139.3	c.232_233insCATGTGC	p.Leu78ProfsTer118	frameshift_variant	1/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.232_233insCATGTGC	p.Leu78ProfsTer118	frameshift_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.232_233insCATGTGC	p.Leu78ProfsTer118	frameshift_variant	1/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.232_233insCATGTGC	p.Leu78ProfsTer118	frameshift_variant	1/2	1		A2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 98

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 454904). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu78Profs*118) in the DNAAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAAF2 are known to be pathogenic (PMID: 19052621, 24498942). -

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: rs1555328130; hg19: chr14-50101635;