14-49634887-C-T
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_018139.3(DNAAF2):c.263G>A(p.Cys88Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,549,632 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00053 ( 1 hom., cov: 35)
Exomes 𝑓: 0.000063 ( 1 hom. )
Consequence
DNAAF2
NM_018139.3 missense
NM_018139.3 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 5.60
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 Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.15856865).
BP6
Variant 14-49634887-C-T is Benign according to our data. Variant chr14-49634887-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313289.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000525 (80/152358) while in subpopulation AFR AF= 0.00183 (76/41586). AF 95% confidence interval is 0.0015. There are 1 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF2 | NM_018139.3 | c.263G>A | p.Cys88Tyr | missense_variant | 1/3 | ENST00000298292.13 | |
DNAAF2 | NM_001083908.2 | c.263G>A | p.Cys88Tyr | missense_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF2 | ENST00000298292.13 | c.263G>A | p.Cys88Tyr | missense_variant | 1/3 | 1 | NM_018139.3 | P2 | |
DNAAF2 | ENST00000406043.3 | c.263G>A | p.Cys88Tyr | missense_variant | 1/2 | 1 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000525 AC: 80AN: 152240Hom.: 1 Cov.: 35
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GnomAD3 exomes AF: 0.0000887 AC: 13AN: 146592Hom.: 0 AF XY: 0.0000506 AC XY: 4AN XY: 79088
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GnomAD4 exome AF: 0.0000630 AC: 88AN: 1397274Hom.: 1 Cov.: 98 AF XY: 0.0000566 AC XY: 39AN XY: 689090
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GnomAD4 genome AF: 0.000525 AC: 80AN: 152358Hom.: 1 Cov.: 35 AF XY: 0.000537 AC XY: 40AN XY: 74510
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 02, 2018 | The p.C88Y variant (also known as c.263G>A), located in coding exon 1 of the DNAAF2 gene, results from a G to A substitution at nucleotide position 263. The cysteine at codon 88 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Primary ciliary dyskinesia 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at