9-421032-C-G

Position:

• chr9-421032-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.4107C>G​(p.Leu1369Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 1,613,794 control chromosomes in the GnomAD database, including 271,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18331 hom., cov: 32)
  • Exomes 𝑓: 0.58 (253432 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.58

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-421032-C-G is Benign according to our data. Variant chr9-421032-C-G is described in ClinVar as [Benign]. Clinvar id is 178769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-421032-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.4107C>G	p.Leu1369Leu	synonymous_variant	32/48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.4107C>G	p.Leu1369Leu	synonymous_variant	32/48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68338 AN: 151964 Hom.: 18331 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.723

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.483

GnomAD3 exomes AF: 0.509 AC: 127876 AN: 251430 Hom.: 35045 AF XY: 0.518 AC XY: 70427 AN XY: 135890

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.512

Gnomad EAS exome AF: 0.490

Gnomad SAS exome AF: 0.433

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.580 AC: 847787 AN: 1461710 Hom.: 253432 Cov.: 57 AF XY: 0.577 AC XY: 419256 AN XY: 727162

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.401

Gnomad4 ASJ exome AF: 0.513

Gnomad4 EAS exome AF: 0.424

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.491

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.550

GnomAD4 genome AF: 0.449 AC: 68350 AN: 152084 Hom.: 18331 Cov.: 32 AF XY: 0.442 AC XY: 32864 AN XY: 74326

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.482

Alfa AF: 0.564 Hom.: 8219

Bravo AF: 0.437

Asia WGS AF: 0.396 AC: 1377 AN: 3478

EpiCase AF: 0.614

EpiControl AF: 0.616

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 63. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu1369Leu in exon 32 of DOCK8: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 38.7% (3325/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2297079). -

Combined immunodeficiency due to DOCK8 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Aug 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	7.1
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2297079; hg19: chr9-421032; COSMIC: COSV66620179;