rs149918318

Variant names:

• chr9-304628-G-A
• rs149918318
• NM_203447.4:c.452G>A
• DOCK8 p.Arg151Gln

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_203447.4(DOCK8):​c.452G>A​(p.Arg151Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00176 in 1,614,138 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R151R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (9 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 3.91
• Publications: 6 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, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -9 ACMG points.

• BP6: Variant 9-304628-G-A is Benign according to our data. Variant chr9-304628-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366540.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00133 (203/152258) while in subpopulation NFE AF = 0.00219 (149/68024). AF 95% confidence interval is 0.0019. There are 0 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

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.452G>A	p.Arg151Gln	missense	Exon 5 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.248G>A	p.Arg83Gln	missense	Exon 4 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.248G>A	p.Arg83Gln	missense	Exon 4 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.452G>A	p.Arg151Gln	missense	Exon 5 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.248G>A	p.Arg83Gln	missense	Exon 4 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.248G>A	p.Arg83Gln	missense	Exon 5 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00139 AC: 350 AN: 251386 AF XY: 0.00137

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00181 AC: 2643 AN: 1461880 Hom.: 9 Cov.: 31 AF XY: 0.00177 AC XY: 1288 AN XY: 727244

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00107 AC: 48 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86258

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53418

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00208 AC: 2318 AN: 1112002

Other (OTH) AF: 0.00142 AC: 86 AN: 60396

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00116 AC XY: 86 AN XY: 74438

African (AFR) AF: 0.000409 AC: 17 AN: 41560

American (AMR) AF: 0.00131 AC: 20 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00197 Hom.: 2

Bravo AF: 0.00143

EpiCase AF: 0.00196

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	2	-	not specified (2)
-	1	-	Combined immunodeficiency due to DOCK8 deficiency (1)
-	-	1	DOCK8-related disorder (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.087
Sift	Benign	1.0	T
Sift4G	Benign	0.79	T
Varity_R		0.071
gMVP		0.51
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: -47

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: rs149918318;

hg19: chr9-304628;

COSMIC: COSV105929673;