chr1-160421085-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_020335.3(VANGL2):c.971G>A(p.Arg324Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
VANGL2
NM_020335.3 missense
NM_020335.3 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 9.57
Genes affected
VANGL2 (HGNC:15511): (VANGL planar cell polarity protein 2) The protein encoded by this gene is a membrane protein involved in the regulation of planar cell polarity, especially in the stereociliary bundles of the cochlea. The encoded protein transmits directional signals to individual cells or groups of cells in epithelial sheets. This protein is also involved in the development of the neural plate. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.957
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VANGL2 | NM_020335.3 | c.971G>A | p.Arg324Gln | missense_variant | 6/8 | ENST00000368061.3 | |
VANGL2 | XM_005245357.2 | c.971G>A | p.Arg324Gln | missense_variant | 7/9 | ||
VANGL2 | XM_011509804.2 | c.971G>A | p.Arg324Gln | missense_variant | 6/8 | ||
VANGL2 | XM_047426020.1 | c.971G>A | p.Arg324Gln | missense_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VANGL2 | ENST00000368061.3 | c.971G>A | p.Arg324Gln | missense_variant | 6/8 | 2 | NM_020335.3 | P1 | |
VANGL2 | ENST00000696602.1 | c.1115G>A | p.Arg372Gln | missense_variant | 6/8 | ||||
VANGL2 | ENST00000483408.1 | n.151G>A | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251414Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135892
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727234
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2017 | The R324Q variant in the VANGL2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R324Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R324Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R324Q as a variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0219);
MVP
MPC
ClinPred
D
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