rs12348944

Variant names:

• chr9-377066-C-T
• rs12348944
• NM_203447.4:c.2295C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.2295C>T​(p.Ser765Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,360 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (135 hom., cov: 33)
  • Exomes 𝑓: 0.012 (226 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.81

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 9-377066-C-T is Benign according to our data. Variant chr9-377066-C-T is described in ClinVar as [Benign]. Clinvar id is 137138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-377066-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.2295C>T	p.Ser765Ser	synonymous_variant	Exon 20 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.2295C>T	p.Ser765Ser	synonymous_variant	Exon 20 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4653 AN: 152182 Hom.: 136 Cov.: 33

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0146 AC: 3645 AN: 250216 Hom.: 74 AF XY: 0.0134 AC XY: 1808 AN XY: 135334

Gnomad AFR exome AF: 0.0824

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.00945

Gnomad FIN exome AF: 0.00420

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0123 AC: 18013 AN: 1461060 Hom.: 226 Cov.: 32 AF XY: 0.0119 AC XY: 8668 AN XY: 726854

Gnomad4 AFR exome AF: 0.0826

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.00494

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00946

Gnomad4 FIN exome AF: 0.00427

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0306 AC: 4655 AN: 152300 Hom.: 135 Cov.: 33 AF XY: 0.0290 AC XY: 2163 AN XY: 74478

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0166 Hom.: 58

Bravo AF: 0.0330

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser765Ser in exon 20 of DOCK8: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 7.6% (335/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs12348944). -

Mar 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.18
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs12348944; hg19: chr9-377066;