chr19-11200714-A-G
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_020812.4(DOCK6):c.5939+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,611,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_020812.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOCK6 | NM_020812.4 | c.5939+2T>C | splice_donor_variant | ENST00000294618.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOCK6 | ENST00000294618.12 | c.5939+2T>C | splice_donor_variant | 1 | NM_020812.4 | A2 | |||
DOCK6 | ENST00000587656.6 | c.6044+2T>C | splice_donor_variant | 5 | P3 | ||||
DOCK6 | ENST00000587734.1 | c.75+1175T>C | intron_variant | 5 | |||||
DOCK6 | ENST00000586702.1 | n.842+2T>C | splice_donor_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000211 AC: 52AN: 246000Hom.: 0 AF XY: 0.000202 AC XY: 27AN XY: 133534
GnomAD4 exome AF: 0.000251 AC: 366AN: 1459250Hom.: 0 Cov.: 32 AF XY: 0.000230 AC XY: 167AN XY: 725606
GnomAD4 genome AF: 0.000184 AC: 28AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74326
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25824905, 30111349, 31654484, 29961505, 29924900, 31589614, 28884918) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change affects a donor splice site in intron 46 of the DOCK6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DOCK6 are known to be pathogenic (PMID: 21820096, 25824905). This variant is present in population databases (rs201387914, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Aicardi-GoutieÃÄres syndrome and Adams-Oliver syndrome (PMID: 25824905, 28884918, 30111349). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253047). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Adams-Oliver syndrome 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 05, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 02, 2023 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2021 | The c.5939+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 46 of the DOCK6 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the DOCK6 c.5939+2T>C alteration was observed in 0.02% (58/277380) of total alleles studied, with a frequency of 0.04% (46/127132) in the European (non-Finnish) subpopulation. This alteration has been reported in the literature in combination with other DOCK6 mutations in patients with features consistent with Adams-Oliver syndrome (Jones, 2017; Dugan, 2018). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at