9-215081-T-G

Variant names:

• chr9-215081-T-G
• rs192260189
• NM_203447.4:c.53+52T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_203447.4(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 NM_203447.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.56
• Publications: 1 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=0.0028540492).
• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR,AD gene

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.53+52T>G		intron	N/A	NP_982272.2	Q8NF50-1
	DOCK8-AS1	NR_160804.1		n.670A>C		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.53+52T>G		intron	N/A	ENSP00000394888.3	Q8NF50-1
	DOCK8-AS1	ENST00000382387.4	TSL:6	n.813A>C		non_coding_transcript_exon	Exon 1 of 1
	DOCK8-AS1	ENST00000648587.1		n.661A>C		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes AF: 0.00180 AC: 225 AN: 125322 AF XY: 0.00131

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 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

African (AFR) AF: 0.0435 AC: 1259 AN: 28956

American (AMR) AF: 0.00271 AC: 97 AN: 35838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24486

East Asian (EAS) AF: 0.00 AC: 0 AN: 34280

South Asian (SAS) AF: 0.0000381 AC: 3 AN: 78760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35198

Middle Eastern (MID) AF: 0.000980 AC: 5 AN: 5104

European-Non Finnish (NFE) AF: 0.0000167 AC: 18 AN: 1080452

Other (OTH) AF: 0.00236 AC: 136 AN: 57560

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

African (AFR) AF: 0.0439 AC: 1825 AN: 41558

American (AMR) AF: 0.00418 AC: 64 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-2.6
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
PromoterAI		0.15	Neutral
Varity_R		0.37
gMVP		0.014
Mutation Taster		=99/1	polymorphism

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: rs192260189; hg19: chr9-215081;