rs34390308

Variant names:

• chr9-406999-C-T
• rs34390308
• NM_203447.4:c.3460C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-406999-C-T
• chr9-406999-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_203447.4(DOCK8):​c.3460C>T​(p.Arg1154Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00186 in 1,614,128 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1154H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (12 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 4.71
• Publications: 13 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 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011115372).
• BP6: Variant 9-406999-C-T is Benign according to our data. Variant chr9-406999-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418766.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00188 (287/152258) while in subpopulation SAS AF = 0.00602 (29/4820). AF 95% confidence interval is 0.0043. There are 4 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.3460C>T	p.Arg1154Cys	missense	Exon 28 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.3256C>T	p.Arg1086Cys	missense	Exon 27 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.3160C>T	p.Arg1054Cys	missense	Exon 26 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.3460C>T	p.Arg1154Cys	missense	Exon 28 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.3160C>T	p.Arg1054Cys	missense	Exon 26 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.3160C>T	p.Arg1054Cys	missense	Exon 27 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152142 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00286 AC: 719 AN: 251248 AF XY: 0.00325

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00186 AC: 2723 AN: 1461870 Hom.: 12 Cov.: 32 AF XY: 0.00210 AC XY: 1527 AN XY: 727232

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 651 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00692 AC: 597 AN: 86258

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53402

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5768

European-Non Finnish (NFE) AF: 0.00101 AC: 1118 AN: 1112008

Other (OTH) AF: 0.00290 AC: 175 AN: 60396

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152258 Hom.: 4 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74444

African (AFR) AF: 0.000144 AC: 6 AN: 41554

American (AMR) AF: 0.00327 AC: 50 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00602 AC: 29 AN: 4820

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68010

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00212 Hom.: 6

Bravo AF: 0.00176

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Combined immunodeficiency due to DOCK8 deficiency (3)
-	-	2	not provided (2)
-	-	1	DOCK8-related disorder (1)
-	-	1	not specified (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.48
MPC		0.31
ClinPred		0.10	T
GERP RS		5.6
Varity_R		0.75
gMVP		0.54
Mutation Taster		=84/16	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: rs34390308; hg19: chr9-406999;