rs17673268

Variant names:

• chr9-368128-C-G
• NM_203447.4:c.1790C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-368128-C-G
• chr9-368128-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_203447.4(DOCK8):​c.1790C>G​(p.Ala597Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A597V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39232722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.1790C>G	p.Ala597Gly	missense_variant	Exon 15 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.1790C>G	p.Ala597Gly	missense_variant	Exon 15 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Uncertain:1

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 597 of the DOCK8 protein (p.Ala597Gly). 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. ClinVar contains an entry for this variant (Variation ID: 1716697). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DOCK8 protein function. 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	.;.;D;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.012	.;.;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.52
MutPred		0.49		Gain of relative solvent accessibility (P = 0.0479);.;.;.;
MVP		0.65
MPC		0.29
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.51
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-368128;