NM_203447.4:c.5581-18G>C

Variant names:

• chr9-446352-G-C
• rs10814952
• NM_203447.4:c.5581-18G>C

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.5581-18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,605,654 control chromosomes in the GnomAD database, including 386,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (29786 hom., cov: 33)
  • Exomes 𝑓: 0.70 (357148 hom.)
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.34
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-446352-G-C is Benign according to our data. Variant chr9-446352-G-C is described in ClinVar as Benign. ClinVar VariationId is 263270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 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.5581-18G>C		intron	N/A	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.5377-18G>C		intron	N/A	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.5281-18G>C		intron	N/A	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.5581-18G>C		intron	N/A	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.5281-18G>C		intron	N/A	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.5281-18G>C		intron	N/A	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90367 AN: 151964 Hom.: 29778 Cov.: 33

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.608

GnomAD2 exomes AF: 0.700 AC: 175532 AN: 250910 AF XY: 0.699

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.810

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.985

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.697

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.695 AC: 1010939 AN: 1453574 Hom.: 357148 Cov.: 29 AF XY: 0.695 AC XY: 502838 AN XY: 723784

African (AFR) AF: 0.277 AC: 9219 AN: 33280

American (AMR) AF: 0.801 AC: 35811 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 16153 AN: 26070

East Asian (EAS) AF: 0.991 AC: 39313 AN: 39676

South Asian (SAS) AF: 0.667 AC: 57344 AN: 86024

European-Finnish (FIN) AF: 0.698 AC: 37257 AN: 53372

Middle Eastern (MID) AF: 0.626 AC: 3611 AN: 5764

European-Non Finnish (NFE) AF: 0.698 AC: 770985 AN: 1104604

Other (OTH) AF: 0.686 AC: 41246 AN: 60082

GnomAD4 genome AF: 0.594 AC: 90404 AN: 152080 Hom.: 29786 Cov.: 33 AF XY: 0.601 AC XY: 44708 AN XY: 74346

African (AFR) AF: 0.291 AC: 12068 AN: 41482

American (AMR) AF: 0.738 AC: 11288 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2176 AN: 3468

East Asian (EAS) AF: 0.985 AC: 5103 AN: 5180

South Asian (SAS) AF: 0.676 AC: 3265 AN: 4828

European-Finnish (FIN) AF: 0.690 AC: 7304 AN: 10578

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47152 AN: 67940

Other (OTH) AF: 0.613 AC: 1290 AN: 2106

Alfa AF: 0.588 Hom.: 3708

Bravo AF: 0.586

Asia WGS AF: 0.800 AC: 2781 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Combined immunodeficiency due to DOCK8 deficiency (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.86
DANN	Benign	0.52
PhyloP100		-1.3
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: rs10814952;

hg19: chr9-446352;