rs913703

Variant names:

• chr9-370244-A-G
• rs913703
• NM_203447.4:c.1812A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-370244-A-G
• chr9-370244-A-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.1812A>G​(p.Lys604Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,611,044 control chromosomes in the GnomAD database, including 45,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4279 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41507 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.763
• Publications: 19 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-370244-A-G is Benign according to our data. Variant chr9-370244-A-G is described in ClinVar as Benign. ClinVar VariationId is 137137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.763 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.259 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.1812A>G	p.Lys604Lys	synonymous	Exon 16 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.1608A>G	p.Lys536Lys	synonymous	Exon 15 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.1608A>G	p.Lys536Lys	synonymous	Exon 15 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.1812A>G	p.Lys604Lys	synonymous	Exon 16 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.1608A>G	p.Lys536Lys	synonymous	Exon 15 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.1608A>G	p.Lys536Lys	synonymous	Exon 16 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35477 AN: 152036 Hom.: 4269 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0730

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.217 AC: 54557 AN: 251342 AF XY: 0.221

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.0646

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.234 AC: 341983 AN: 1458890 Hom.: 41507 Cov.: 32 AF XY: 0.236 AC XY: 171044 AN XY: 725966

African (AFR) AF: 0.271 AC: 9056 AN: 33418

American (AMR) AF: 0.197 AC: 8789 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5291 AN: 26112

East Asian (EAS) AF: 0.0791 AC: 3138 AN: 39694

South Asian (SAS) AF: 0.255 AC: 21958 AN: 86202

European-Finnish (FIN) AF: 0.180 AC: 9614 AN: 53408

Middle Eastern (MID) AF: 0.277 AC: 1593 AN: 5756

European-Non Finnish (NFE) AF: 0.242 AC: 268194 AN: 1109282

Other (OTH) AF: 0.238 AC: 14350 AN: 60298

GnomAD4 genome AF: 0.233 AC: 35509 AN: 152154 Hom.: 4279 Cov.: 32 AF XY: 0.230 AC XY: 17094 AN XY: 74362

African (AFR) AF: 0.263 AC: 10922 AN: 41498

American (AMR) AF: 0.219 AC: 3349 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 652 AN: 3472

East Asian (EAS) AF: 0.0732 AC: 379 AN: 5178

South Asian (SAS) AF: 0.252 AC: 1218 AN: 4828

European-Finnish (FIN) AF: 0.177 AC: 1874 AN: 10576

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16238 AN: 68012

Other (OTH) AF: 0.232 AC: 489 AN: 2110

Alfa AF: 0.237 Hom.: 10249

Bravo AF: 0.238

Asia WGS AF: 0.164 AC: 571 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Combined immunodeficiency due to DOCK8 deficiency (1)
-	-	1	not provided (2)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.8
DANN	Benign	0.89
PhyloP100		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=293/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs913703; hg19: chr9-370244; COSMIC: COSV66619880;