rs192260189

Positions:

• chr9-215081-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000432829.7(DOCK8):​c.53+52T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,532,890 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: DOCK8 ENST00000432829.7 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.56

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-AS1 (HGNC:26436): (DOCK8 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028540492).
• BP6: Variant 9-215081-T-G is Benign according to our data. Variant chr9-215081-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 235456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0125 (1908/152256) while in subpopulation AFR AF= 0.0439 (1825/41558). AF 95% confidence interval is 0.0422. There are 40 homozygotes in gnomad4. There are 923 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.53+52T>G		intron_variant		ENST00000432829.7	NP_982272.2
DOCK8-AS1	NR_160804.1	n.670A>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.53+52T>G		intron_variant		1	NM_203447.4	ENSP00000394888
DOCK8-AS1	ENST00000648587.1	n.661A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1908 AN: 152144 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00180 AC: 225 AN: 125322 Hom.: 3 AF XY: 0.00131 AC XY: 92 AN XY: 70376

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000460

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000590

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00110 AC: 1518 AN: 1380634 Hom.: 22 Cov.: 45 AF XY: 0.000935 AC XY: 638 AN XY: 682630

Gnomad4 AFR exome AF: 0.0435

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000381

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.00236

GnomAD4 genome AF: 0.0125 AC: 1908 AN: 152256 Hom.: 40 Cov.: 32 AF XY: 0.0124 AC XY: 923 AN XY: 74458

Gnomad4 AFR AF: 0.0439

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00713 Hom.: 5

Bravo AF: 0.0143

ESP6500AA AF: 0.0188 AC: 55

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00212 AC: 224

Asia WGS AF: 0.00231 AC: 8 AN: 3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.4
DANN	Benign	0.34
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.042
Sift4G	Benign	0.25	T
Polyphen		0.044	B
Vest4		0.044
MVP		0.048
MPC		0.18
ClinPred		0.0079	T
GERP RS		-0.70
Varity_R		0.37
gMVP		0.014

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

Publications

LitVar

Other links and lift over

dbSNP: rs192260189; hg19: chr9-215081;