9-446352-G-C

Position:

• chr9-446352-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.5581-18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,605,654 control chromosomes in the GnomAD database, including 386,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (29786 hom., cov: 33)
  • Exomes 𝑓: 0.70 (357148 hom.)
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.34

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-446352-G-C is Benign according to our data. Variant chr9-446352-G-C is described in ClinVar as [Benign]. Clinvar id is 263270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-446352-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5581-18G>C		intron_variant		ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.5581-18G>C		intron_variant		1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90367 AN: 151964 Hom.: 29778 Cov.: 33

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.608

GnomAD3 exomes AF: 0.700 AC: 175532 AN: 250910 Hom.: 64136 AF XY: 0.699 AC XY: 94883 AN XY: 135666

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.810

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.985

Gnomad SAS exome AF: 0.666

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.697

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.695 AC: 1010939 AN: 1453574 Hom.: 357148 Cov.: 29 AF XY: 0.695 AC XY: 502838 AN XY: 723784

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.801

Gnomad4 ASJ exome AF: 0.620

Gnomad4 EAS exome AF: 0.991

Gnomad4 SAS exome AF: 0.667

Gnomad4 FIN exome AF: 0.698

Gnomad4 NFE exome AF: 0.698

Gnomad4 OTH exome AF: 0.686

GnomAD4 genome AF: 0.594 AC: 90404 AN: 152080 Hom.: 29786 Cov.: 33 AF XY: 0.601 AC XY: 44708 AN XY: 74346

Gnomad4 AFR AF: 0.291

Gnomad4 AMR AF: 0.738

Gnomad4 ASJ AF: 0.627

Gnomad4 EAS AF: 0.985

Gnomad4 SAS AF: 0.676

Gnomad4 FIN AF: 0.690

Gnomad4 NFE AF: 0.694

Gnomad4 OTH AF: 0.613

Alfa AF: 0.588 Hom.: 3708

Bravo AF: 0.586

Asia WGS AF: 0.800 AC: 2781 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 94% of patients studied by a panel of primary immunodeficiencies. Number of patients: 90. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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	-0.91
CADD	Benign	0.86
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs10814952; hg19: chr9-446352;