NM_203447.4:c.699T>C

Variant names:

• chr9-312124-T-C
• rs2039045
• NM_203447.4:c.699T>C

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.699T>C​(p.Asn233Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,614,032 control chromosomes in the GnomAD database, including 30,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3100 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27038 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.300
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-312124-T-C is Benign according to our data. Variant chr9-312124-T-C is described in ClinVar as Benign. ClinVar VariationId is 137157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 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.699T>C	p.Asn233Asn	synonymous	Exon 6 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.495T>C	p.Asn165Asn	synonymous	Exon 5 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.495T>C	p.Asn165Asn	synonymous	Exon 5 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.699T>C	p.Asn233Asn	synonymous	Exon 6 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.495T>C	p.Asn165Asn	synonymous	Exon 5 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.495T>C	p.Asn165Asn	synonymous	Exon 6 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29500 AN: 152070 Hom.: 3100 Cov.: 33

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.00713

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.165 AC: 41407 AN: 251196 AF XY: 0.165

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.00561

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.187 AC: 274011 AN: 1461844 Hom.: 27038 Cov.: 33 AF XY: 0.186 AC XY: 135558 AN XY: 727224

African (AFR) AF: 0.245 AC: 8201 AN: 33480

American (AMR) AF: 0.164 AC: 7343 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3302 AN: 26136

East Asian (EAS) AF: 0.00416 AC: 165 AN: 39700

South Asian (SAS) AF: 0.156 AC: 13423 AN: 86258

European-Finnish (FIN) AF: 0.153 AC: 8191 AN: 53414

Middle Eastern (MID) AF: 0.194 AC: 1120 AN: 5766

European-Non Finnish (NFE) AF: 0.199 AC: 221280 AN: 1111970

Other (OTH) AF: 0.182 AC: 10986 AN: 60396

GnomAD4 genome AF: 0.194 AC: 29508 AN: 152188 Hom.: 3100 Cov.: 33 AF XY: 0.190 AC XY: 14099 AN XY: 74398

African (AFR) AF: 0.246 AC: 10203 AN: 41512

American (AMR) AF: 0.182 AC: 2781 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 394 AN: 3472

East Asian (EAS) AF: 0.00734 AC: 38 AN: 5176

South Asian (SAS) AF: 0.160 AC: 770 AN: 4822

European-Finnish (FIN) AF: 0.151 AC: 1601 AN: 10600

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13134 AN: 67998

Other (OTH) AF: 0.184 AC: 388 AN: 2106

Alfa AF: 0.173 Hom.: 1558

Bravo AF: 0.198

Asia WGS AF: 0.0940 AC: 327 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.194

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.8
DANN	Benign	0.48
PhyloP100		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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

Other links and lift over

dbSNP: rs2039045; hg19: chr9-312124; COSMIC: COSV66634218;