rs10491684

Variant names:

• chr9-449798-G-A
• rs10491684
• NM_203447.4:c.5832G>A
• DOCK8 p.Pro1944Pro

Your query was ambiguous. Multiple possible variants found:

• chr9-449798-G-A
• chr9-449798-G-C
• chr9-449798-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.5832G>A​(p.Pro1944Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,612,724 control chromosomes in the GnomAD database, including 4,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (748 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3883 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.905
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 9-449798-G-A is Benign according to our data. Variant chr9-449798-G-A is described in ClinVar as Benign. ClinVar VariationId is 137153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.905 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 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.5832G>A	p.Pro1944Pro	synonymous	Exon 45 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.5628G>A	p.Pro1876Pro	synonymous	Exon 44 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.5532G>A	p.Pro1844Pro	synonymous	Exon 43 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.5832G>A	p.Pro1944Pro	synonymous	Exon 45 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.5532G>A	p.Pro1844Pro	synonymous	Exon 43 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.5532G>A	p.Pro1844Pro	synonymous	Exon 44 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.0900 AC: 13675 AN: 151982 Hom.: 744 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0295

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0729

Gnomad OTH AF: 0.0999

GnomAD2 exomes AF: 0.0673 AC: 16929 AN: 251396 AF XY: 0.0665

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0449

Gnomad ASJ exome AF: 0.0924

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0860

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0699 AC: 102065 AN: 1460624 Hom.: 3883 Cov.: 32 AF XY: 0.0695 AC XY: 50471 AN XY: 726642

African (AFR) AF: 0.149 AC: 4988 AN: 33436

American (AMR) AF: 0.0478 AC: 2140 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0922 AC: 2409 AN: 26130

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0422 AC: 3638 AN: 86202

European-Finnish (FIN) AF: 0.0854 AC: 4560 AN: 53402

Middle Eastern (MID) AF: 0.0862 AC: 412 AN: 4778

European-Non Finnish (NFE) AF: 0.0716 AC: 79632 AN: 1111962

Other (OTH) AF: 0.0709 AC: 4277 AN: 60290

GnomAD4 genome AF: 0.0900 AC: 13686 AN: 152100 Hom.: 748 Cov.: 32 AF XY: 0.0869 AC XY: 6459 AN XY: 74364

African (AFR) AF: 0.150 AC: 6217 AN: 41470

American (AMR) AF: 0.0566 AC: 865 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0297 AC: 143 AN: 4816

European-Finnish (FIN) AF: 0.0844 AC: 893 AN: 10580

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0729 AC: 4955 AN: 67990

Other (OTH) AF: 0.0993 AC: 210 AN: 2114

Alfa AF: 0.0818 Hom.: 1266

Bravo AF: 0.0914

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0750

EpiControl AF: 0.0758

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Combined immunodeficiency due to DOCK8 deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.3
DANN	Benign	0.82
PhyloP100		-0.91
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs10491684;

hg19: chr9-449798;

COSMIC: COSV66619896;

COSMIC: COSV66619896;