rs636922

Variant names:

• chr9-215269-A-C
• rs636922
• ENST00000382329.2:c.-299A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000382329.2(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 ENST00000382329.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.27
• Publications: 29 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-AS1 (HGNC:26436): (DOCK8 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.53+240A>C		intron_variant	Intron 1 of 47	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.53+240A>C		intron_variant	Intron 1 of 47	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

GnomAD2 exomes AF: 0.241 AC: 55070 AN: 228320 AF XY: 0.242

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 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

African (AFR) AF: 0.0400 AC: 1317 AN: 32914

American (AMR) AF: 0.233 AC: 10143 AN: 43586

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3920 AN: 25830

East Asian (EAS) AF: 0.323 AC: 12566 AN: 38900

South Asian (SAS) AF: 0.193 AC: 16419 AN: 84868

European-Finnish (FIN) AF: 0.321 AC: 16644 AN: 51886

Middle Eastern (MID) AF: 0.215 AC: 1229 AN: 5720

European-Non Finnish (NFE) AF: 0.271 AC: 299921 AN: 1108248

Other (OTH) AF: 0.247 AC: 14808 AN: 59986

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

African (AFR) AF: 0.0495 AC: 2056 AN: 41504

American (AMR) AF: 0.217 AC: 3318 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 499 AN: 3464

East Asian (EAS) AF: 0.338 AC: 1729 AN: 5116

South Asian (SAS) AF: 0.182 AC: 875 AN: 4812

European-Finnish (FIN) AF: 0.314 AC: 3316 AN: 10552

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18474 AN: 67880

Other (OTH) AF: 0.219 AC: 462 AN: 2108

Alfa AF: 0.250 Hom.: 13771

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-3.3
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
PromoterAI		-0.0020	Neutral
Varity_R		0.42
gMVP		0.047
Mutation Taster		=100/0	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: rs636922; hg19: chr9-215269; COSMIC: COSV66688009;