chr9-214990-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_203447.4(DOCK8):c.14C>G(p.Pro5Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000076 in 1,446,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P5P) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000076 ( 0 hom. )
Consequence
DOCK8
NM_203447.4 missense
NM_203447.4 missense
Scores
1
4
10
Clinical Significance
Conservation
PhyloP100: 3.82
Genes affected
DOCK8 (HGNC:19191): (dedicator of cytokinesis 8) This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOCK8 | NM_203447.4 | c.14C>G | p.Pro5Arg | missense_variant | 1/48 | ENST00000432829.7 | |
DOCK8-AS1 | NR_160804.1 | n.761G>C | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOCK8 | ENST00000432829.7 | c.14C>G | p.Pro5Arg | missense_variant | 1/48 | 1 | NM_203447.4 | ||
DOCK8-AS1 | ENST00000648587.1 | n.752G>C | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome AF: 0.00000760 AC: 11AN: 1446806Hom.: 0 Cov.: 110 AF XY: 0.00000556 AC XY: 4AN XY: 719582
GnomAD4 exome
AF:
AC:
11
AN:
1446806
Hom.:
Cov.:
110
AF XY:
AC XY:
4
AN XY:
719582
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Combined immunodeficiency due to DOCK8 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 19, 2022 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 5 of the DOCK8 protein (p.Pro5Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DOCK8-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T
MetaSVM
Benign
T
MutationTaster
Benign
D;N;N
PrimateAI
Pathogenic
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of MoRF binding (P = 0);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at