14-96855353-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_003384.3(VRK1):c.706G>A(p.Val236Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251274Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135814
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461698Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727158
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Pontocerebellar hypoplasia type 1A Pathogenic:3Uncertain:1
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Segregates with the phenotype in affected family -
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 236 of the VRK1 protein (p.Val236Met). This variant is present in population databases (rs771364038, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of distal hereditary motor neuropathy (PMID: 24126608; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218924). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects VRK1 function (PMID: 31527692). For these reasons, this variant has been classified as Pathogenic. -
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Pontocerebellar hypoplasia type 1A;C5882703:Neuronopathy, distal hereditary motor, autosomal recessive 10 Pathogenic:1
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect, as the V236M variant results in loss of kinase activity (PMID: 31527692); Reported in trans with another VRK1 variant in two siblings with microcephaly and severe, rapidly progressive distal symmetric polyneuropathy with normal intellect in published literature (PMID: 24126608); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 24970098, 27281532, 25609612, 26583493, 34169149, 30617279, 30847374, 31178479, 27149842, 35641352, 31560180, 31090908, 24126608, 31527692) -
Neuronopathy, distal hereditary motor, autosomal recessive 10 Pathogenic:1
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Inborn genetic diseases Uncertain:1
The c.706G>A (p.V236M) alteration is located in exon 8 (coding exon 7) of the VRK1 gene. This alteration results from a G to A substitution at nucleotide position 706, causing the valine (V) at amino acid position 236 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at