rs869312169

Variant names:

• chr9-452067-C-CT
• rs869312169
• NM_203447.4:c.6019dupT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_203447.4(DOCK8):​c.6019dupT​(p.Tyr2007LeufsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000759 in 1,449,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: DOCK8 NM_203447.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.93
• Publications: 3 publications found

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]

DOCK8 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-452067-C-CT is Pathogenic according to our data. Variant chr9-452067-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 224488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.6019dupT	p.Tyr2007LeufsTer12	frameshift_variant	Exon 46 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.6019dupT	p.Tyr2007LeufsTer12	frameshift_variant	Exon 46 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000759 AC: 11 AN: 1449366 Hom.: 0 Cov.: 31 AF XY: 0.00000693 AC XY: 5 AN XY: 721046

African (AFR) AF: 0.00 AC: 0 AN: 32598

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25652

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000906 AC: 10 AN: 1103828

Other (OTH) AF: 0.0000168 AC: 1 AN: 59484

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to DOCK8 deficiency Pathogenic:1

Aug 25, 2015

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pathogenic:1

Dec 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr2007Leufs*12) in the DOCK8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DOCK8 are known to be pathogenic (PMID: 14722525, 19776401). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of DOCK8-related conditions (PMID: 24797421). This variant is also known as c.5815_5816insT. ClinVar contains an entry for this variant (Variation ID: 224488). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869312169; hg19: chr9-452067;