rs2360712

Variant names:

• chr9-433978-A-G
• rs2360712
• NM_203447.4:c.4886+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-433978-A-G
• chr9-433978-A-C
• chr9-433978-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.4886+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,607,664 control chromosomes in the GnomAD database, including 463,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38454 hom., cov: 32)
  • Exomes 𝑓: 0.76 (425071 hom.)
• Consequence: DOCK8 NM_203447.4 splice_region, intron
• Scores: Splicing: ADA: 0.004113
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 2.00
• Publications: 13 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 9-433978-A-G is Benign according to our data. Variant chr9-433978-A-G is described in ClinVar as Benign. ClinVar VariationId is 163177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 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.4886+3A>G		splice_region intron	N/A	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.4682+3A>G		splice_region intron	N/A	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.4586+3A>G		splice_region 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.4886+3A>G		splice_region intron	N/A	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.4586+3A>G		splice_region intron	N/A	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.4586+3A>G		splice_region intron	N/A	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106442 AN: 151928 Hom.: 38438 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.716

GnomAD2 exomes AF: 0.767 AC: 192569 AN: 251210 AF XY: 0.763

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.852

Gnomad ASJ exome AF: 0.709

Gnomad EAS exome AF: 0.985

Gnomad FIN exome AF: 0.796

Gnomad NFE exome AF: 0.765

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.761 AC: 1108163 AN: 1455618 Hom.: 425071 Cov.: 31 AF XY: 0.759 AC XY: 550337 AN XY: 724626

African (AFR) AF: 0.498 AC: 16608 AN: 33364

American (AMR) AF: 0.846 AC: 37837 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 18533 AN: 26100

East Asian (EAS) AF: 0.981 AC: 38927 AN: 39688

South Asian (SAS) AF: 0.688 AC: 59205 AN: 86108

European-Finnish (FIN) AF: 0.795 AC: 42417 AN: 53376

Middle Eastern (MID) AF: 0.708 AC: 4081 AN: 5762

European-Non Finnish (NFE) AF: 0.764 AC: 845089 AN: 1106298

Other (OTH) AF: 0.755 AC: 45466 AN: 60204

GnomAD4 genome AF: 0.700 AC: 106507 AN: 152046 Hom.: 38454 Cov.: 32 AF XY: 0.705 AC XY: 52415 AN XY: 74326

African (AFR) AF: 0.508 AC: 21052 AN: 41418

American (AMR) AF: 0.795 AC: 12164 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2536 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5083 AN: 5182

South Asian (SAS) AF: 0.688 AC: 3316 AN: 4818

European-Finnish (FIN) AF: 0.788 AC: 8340 AN: 10582

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51698 AN: 67966

Other (OTH) AF: 0.719 AC: 1515 AN: 2108

Alfa AF: 0.739 Hom.: 40346

Bravo AF: 0.695

Asia WGS AF: 0.821 AC: 2854 AN: 3478

EpiCase AF: 0.749

EpiControl AF: 0.761

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Combined immunodeficiency due to DOCK8 deficiency (2)
-	-	2	not provided (3)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.20
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: rs2360712; hg19: chr9-433978;