rs145573166

Variant names:

• chr9-463649-A-G
• rs145573166
• NM_203447.4:c.6201A>G
• DOCK8 p.Glu2067Glu

Your query was ambiguous. Multiple possible variants found:

• chr9-463649-A-G
• chr9-463649-A-C
• chr9-463649-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_203447.4(DOCK8):​c.6201A>G​(p.Glu2067Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,664 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.455
• 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-AS2 (HGNC:55822): (DOCK8 antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 9-463649-A-G is Benign according to our data. Variant chr9-463649-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.455 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00208 (317/152244) while in subpopulation AFR AF = 0.00486 (202/41536). AF 95% confidence interval is 0.00431. There are 1 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.6201A>G	p.Glu2067Glu	synonymous	Exon 47 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.5997A>G	p.Glu1999Glu	synonymous	Exon 46 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.5901A>G	p.Glu1967Glu	synonymous	Exon 45 of 46	NP_001177387.1	Q8NF50-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.6201A>G	p.Glu2067Glu	synonymous	Exon 47 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.5901A>G	p.Glu1967Glu	synonymous	Exon 45 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000495184.5	TSL:1	n.8156A>G		non_coding_transcript_exon	Exon 45 of 46

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00106 AC: 261 AN: 246772 AF XY: 0.00105

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000995

GnomAD4 exome AF: 0.00149 AC: 2180 AN: 1461420 Hom.: 6 Cov.: 32 AF XY: 0.00143 AC XY: 1037 AN XY: 726970

African (AFR) AF: 0.00520 AC: 174 AN: 33476

American (AMR) AF: 0.000380 AC: 17 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.0000755 AC: 4 AN: 53010

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00171 AC: 1904 AN: 1111988

Other (OTH) AF: 0.00109 AC: 66 AN: 60392

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74440

African (AFR) AF: 0.00486 AC: 202 AN: 41536

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68002

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00236

EpiCase AF: 0.00207

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Combined immunodeficiency due to DOCK8 deficiency (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.8
DANN	Benign	0.59
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145573166;

hg19: chr9-463649;

COSMIC: COSV66622994;

COSMIC: COSV66622994;