chr14-49633705-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018139.3(DNAAF2):​c.1445G>C​(p.Gly482Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

DNAAF2
NM_018139.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.898
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.055983752).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAAF2NM_018139.3 linkuse as main transcriptc.1445G>C p.Gly482Ala missense_variant 1/3 ENST00000298292.13 NP_060609.2
DNAAF2NM_001083908.2 linkuse as main transcriptc.1445G>C p.Gly482Ala missense_variant 1/2 NP_001077377.1
DNAAF2NM_001378453.1 linkuse as main transcriptc.-427G>C 5_prime_UTR_variant 1/2 NP_001365382.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAAF2ENST00000298292.13 linkuse as main transcriptc.1445G>C p.Gly482Ala missense_variant 1/31 NM_018139.3 ENSP00000298292 P2Q9NVR5-1
DNAAF2ENST00000406043.3 linkuse as main transcriptc.1445G>C p.Gly482Ala missense_variant 1/21 ENSP00000384862 A2Q9NVR5-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
92
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 27, 2017In 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DNAAF2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 482 of the DNAAF2 protein (p.Gly482Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.81
CADD
Benign
0.044
DANN
Benign
0.56
DEOGEN2
Benign
0.0020
T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.013
N
LIST_S2
Benign
0.47
T;T
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.056
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.9
L;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.018
Sift
Benign
0.73
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.0090
B;B
Vest4
0.073
MutPred
0.34
Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);
MVP
0.15
MPC
0.55
ClinPred
0.056
T
GERP RS
-2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.026
gMVP
0.55

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1427910863; hg19: chr14-50100423; API