rs636922

Positions:

• chr9-215269-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000382329(DOCK8):​c.-299A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,603,846 control chromosomes in the GnomAD database, including 54,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3984 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50724 hom.)
• Consequence: DOCK8 ENST00000382329 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.27

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029010475).
• BP6: Variant 9-215269-A-C is Benign according to our data. Variant chr9-215269-A-C is described in ClinVar as [Benign]. Clinvar id is 676901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.53+240A>C		intron_variant		ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.53+240A>C		intron_variant		1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31038 AN: 151790 Hom.: 3986 Cov.: 32

Gnomad AFR AF: 0.0497

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.241 AC: 55070 AN: 228320 Hom.: 7141 AF XY: 0.242 AC XY: 30221 AN XY: 125040

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.316

Gnomad SAS exome AF: 0.186

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.260 AC: 376967 AN: 1451938 Hom.: 50724 Cov.: 44 AF XY: 0.258 AC XY: 186357 AN XY: 721850

Gnomad4 AFR exome AF: 0.0400

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.323

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.204 AC: 31033 AN: 151908 Hom.: 3984 Cov.: 32 AF XY: 0.208 AC XY: 15461 AN XY: 74236

Gnomad4 AFR AF: 0.0495

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.219

Alfa AF: 0.255 Hom.: 9696

Bravo AF: 0.194

TwinsUK AF: 0.257 AC: 953

ALSPAC AF: 0.278 AC: 1072

ESP6500AA AF: 0.0546 AC: 240

ESP6500EA AF: 0.248 AC: 2130

ExAC AF: 0.234 AC: 28297

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.18
DANN	Benign	0.85
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.067
Sift4G	Pathogenic	0.0	D
Polyphen		0.089	B
Vest4		0.049
MPC		0.65
ClinPred		0.0082	T
GERP RS		-6.2
Varity_R		0.42
gMVP		0.047

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: rs636922; hg19: chr9-215269; COSMIC: COSV66688009;