rs116920018

Variant names:

• chr9-420579-A-G
• rs116920018
• NM_203447.4:c.4019A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_203447.4(DOCK8):​c.4019A>G​(p.Tyr1340Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,156 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (19 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 9.22
• Publications: 12 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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, Cadd, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.026553571).
• BP6: Variant 9-420579-A-G is Benign according to our data. Variant chr9-420579-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372357.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00274 (417/152298) while in subpopulation NFE AF = 0.00365 (248/68030). AF 95% confidence interval is 0.00327. There are 2 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4019A>G	p.Tyr1340Cys	missense	Exon 31 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.3815A>G	p.Tyr1272Cys	missense	Exon 30 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.3719A>G	p.Tyr1240Cys	missense	Exon 29 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.4019A>G	p.Tyr1340Cys	missense	Exon 31 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.3719A>G	p.Tyr1240Cys	missense	Exon 29 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.3719A>G	p.Tyr1240Cys	missense	Exon 30 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152180 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00744

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00365

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00271 AC: 681 AN: 251468 AF XY: 0.00283

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00684

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00366 AC: 5351 AN: 1461858 Hom.: 19 Cov.: 31 AF XY: 0.00356 AC XY: 2592 AN XY: 727234

African (AFR) AF: 0.000329 AC: 11 AN: 33478

American (AMR) AF: 0.00197 AC: 88 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00220 AC: 190 AN: 86258

European-Finnish (FIN) AF: 0.00594 AC: 317 AN: 53396

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00409 AC: 4545 AN: 1112002

Other (OTH) AF: 0.00323 AC: 195 AN: 60396

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152298 Hom.: 2 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74472

African (AFR) AF: 0.000818 AC: 34 AN: 41544

American (AMR) AF: 0.00248 AC: 38 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.00744 AC: 79 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00365 AC: 248 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00305 Hom.: 5

Bravo AF: 0.00235

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00253 AC: 307

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not specified (4)
-	1	1	Combined immunodeficiency due to DOCK8 deficiency (2)
-	-	2	not provided (2)
-	-	1	DOCK8-related disorder (1)
-	-	1	Intellectual disability (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.62
MPC		0.33
ClinPred		0.088	T
GERP RS		6.0
Varity_R		0.78
gMVP		0.82
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs116920018; hg19: chr9-420579; COSMIC: COSV101210081;