rs529208

Variant names:

• chr9-286593-C-A
• rs529208
• NM_203447.4:c.289C>A
• DOCK8 p.Pro97Thr

Your query was ambiguous. Multiple possible variants found:

• chr9-286593-C-A
• chr9-286593-C-G
• chr9-286593-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.289C>A​(p.Pro97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 1,613,234 control chromosomes in the GnomAD database, including 204,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P97A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.48 (18265 hom., cov: 32)
  • Exomes 𝑓: 0.50 (185805 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 3.24
• Publications: 50 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: Ambry Genetics, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.5923292E-6).
• BP6: Variant 9-286593-C-A is Benign according to our data. Variant chr9-286593-C-A is described in ClinVar as Benign. ClinVar VariationId is 178766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203447.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	NM_203447.4	MANE Select	c.289C>A	p.Pro97Thr	missense	Exon 3 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.85C>A	p.Pro29Thr	missense	Exon 2 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.85C>A	p.Pro29Thr	missense	Exon 2 of 46	NP_001177387.1	Q8NF50-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.289C>A	p.Pro97Thr	missense	Exon 3 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.85C>A	p.Pro29Thr	missense	Exon 2 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.85C>A	p.Pro29Thr	missense	Exon 3 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73595 AN: 151746 Hom.: 18252 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.515

GnomAD2 exomes AF: 0.525 AC: 132036 AN: 251288 AF XY: 0.525

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.543

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.746

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.501 AC: 732667 AN: 1461370 Hom.: 185805 Cov.: 52 AF XY: 0.503 AC XY: 365670 AN XY: 726998

African (AFR) AF: 0.402 AC: 13455 AN: 33452

American (AMR) AF: 0.540 AC: 24151 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 12256 AN: 26122

East Asian (EAS) AF: 0.743 AC: 29495 AN: 39688

South Asian (SAS) AF: 0.545 AC: 47048 AN: 86250

European-Finnish (FIN) AF: 0.563 AC: 30056 AN: 53404

Middle Eastern (MID) AF: 0.548 AC: 3157 AN: 5762

European-Non Finnish (NFE) AF: 0.488 AC: 542400 AN: 1111620

Other (OTH) AF: 0.508 AC: 30649 AN: 60370

GnomAD4 genome AF: 0.485 AC: 73636 AN: 151864 Hom.: 18265 Cov.: 32 AF XY: 0.492 AC XY: 36526 AN XY: 74206

African (AFR) AF: 0.404 AC: 16737 AN: 41388

American (AMR) AF: 0.519 AC: 7921 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1651 AN: 3466

East Asian (EAS) AF: 0.735 AC: 3789 AN: 5156

South Asian (SAS) AF: 0.560 AC: 2695 AN: 4812

European-Finnish (FIN) AF: 0.572 AC: 6033 AN: 10544

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.491 AC: 33323 AN: 67934

Other (OTH) AF: 0.520 AC: 1094 AN: 2104

Alfa AF: 0.486 Hom.: 66564

Bravo AF: 0.478

Asia WGS AF: 0.650 AC: 2260 AN: 3478

EpiCase AF: 0.489

EpiControl AF: 0.482

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Combined immunodeficiency due to DOCK8 deficiency (4)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0000036	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.20
Sift	Benign	0.052	T
Sift4G	Uncertain	0.010	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.30
gMVP		0.46
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs529208; hg19: chr9-286593; COSMIC: COSV66633951;