9-214864-C-T

Variant names:

• chr9-214864-C-T
• rs2236547
• XM_047423927.1:c.-152+3548C>T

Variant summary

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

The ENST00000469197.5(DOCK8):​n.-113C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,604,274 control chromosomes in the GnomAD database, including 41,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4754 hom., cov: 34)
  • Exomes 𝑓: 0.22 (36489 hom.)
• Consequence: DOCK8 ENST00000469197.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0540
• Publications: 25 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=6.2680244E-4).
• BP6: Variant 9-214864-C-T is Benign according to our data. Variant chr9-214864-C-T is described in ClinVar as Benign. ClinVar VariationId is 369626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000469197.5. 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-AS1	NR_160804.1		n.887G>A		non_coding_transcript_exon	Exon 1 of 1
	DOCK8	NM_203447.4	MANE Select	c.-113C>T		upstream_gene	N/A	NP_982272.2	Q8NF50-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000469197.5	TSL:5	n.-113C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000418587.1	F8WC95
	DOCK8-AS1	ENST00000382387.4	TSL:6	n.1030G>A		non_coding_transcript_exon	Exon 1 of 1
	DOCK8	ENST00000469197.5	TSL:5	n.-113C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000418587.1	F8WC95

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37095 AN: 151916 Hom.: 4746 Cov.: 34

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.255 AC: 59015 AN: 231510 AF XY: 0.253

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.389

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.217 AC: 315097 AN: 1452246 Hom.: 36489 Cov.: 105 AF XY: 0.220 AC XY: 159020 AN XY: 722444

African (AFR) AF: 0.295 AC: 9450 AN: 32074

American (AMR) AF: 0.347 AC: 15219 AN: 43846

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6306 AN: 25866

East Asian (EAS) AF: 0.381 AC: 14772 AN: 38742

South Asian (SAS) AF: 0.328 AC: 27817 AN: 84932

European-Finnish (FIN) AF: 0.173 AC: 8988 AN: 51836

Middle Eastern (MID) AF: 0.267 AC: 1532 AN: 5744

European-Non Finnish (NFE) AF: 0.196 AC: 216996 AN: 1109138

Other (OTH) AF: 0.233 AC: 14017 AN: 60068

GnomAD4 genome AF: 0.244 AC: 37138 AN: 152028 Hom.: 4754 Cov.: 34 AF XY: 0.246 AC XY: 18250 AN XY: 74314

African (AFR) AF: 0.288 AC: 11955 AN: 41468

American (AMR) AF: 0.294 AC: 4493 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 875 AN: 3472

East Asian (EAS) AF: 0.391 AC: 2013 AN: 5150

South Asian (SAS) AF: 0.337 AC: 1624 AN: 4820

European-Finnish (FIN) AF: 0.175 AC: 1849 AN: 10576

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.198 AC: 13443 AN: 67940

Other (OTH) AF: 0.277 AC: 584 AN: 2108

Alfa AF: 0.214 Hom.: 7688

Bravo AF: 0.255

TwinsUK AF: 0.186 AC: 689

ALSPAC AF: 0.197 AC: 760

ESP6500AA AF: 0.278 AC: 1030

ESP6500EA AF: 0.185 AC: 1388

ExAC AF: 0.254 AC: 29793

Asia WGS AF: 0.395 AC: 1373 AN: 3468

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hyper-IgE syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.90
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.00063	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.054
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.097
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.15
ClinPred		0.0027	T
GERP RS		3.5
PromoterAI		0.024	Neutral
Varity_R		0.13
gMVP		0.0061
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2236547; hg19: chr9-214864; COSMIC: COSV66687989; COSMIC: COSV66687989;