rs369449324

Variant names:

• chr9-377154-G-C
• rs369449324
• NM_203447.4:c.2383G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-377154-G-C
• chr9-377154-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_203447.4(DOCK8):​c.2383G>C​(p.Val795Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,606,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: 2.29
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022010624).
• BP6: Variant 9-377154-G-C is Benign according to our data. Variant chr9-377154-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 577327.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000853 (13/152320) while in subpopulation EAS AF = 0.00193 (10/5188). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.2383G>C	p.Val795Leu	missense	Exon 20 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.2179G>C	p.Val727Leu	missense	Exon 19 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.2179G>C	p.Val727Leu	missense	Exon 19 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.2383G>C	p.Val795Leu	missense	Exon 20 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.2179G>C	p.Val727Leu	missense	Exon 19 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.2179G>C	p.Val727Leu	missense	Exon 20 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000177 AC: 43 AN: 243566 AF XY: 0.000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1453912 Hom.: 0 Cov.: 33 AF XY: 0.000105 AC XY: 76 AN XY: 723404

African (AFR) AF: 0.0000299 AC: 1 AN: 33448

American (AMR) AF: 0.0000672 AC: 3 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5388

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111720

Other (OTH) AF: 0.000863 AC: 52 AN: 60274

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	DOCK8-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	Not specified (1)
-	-	-	Combined immunodeficiency due to DOCK8 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.0064
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.088
Sift	Benign	0.65	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.36
MutPred		0.47		Loss of ubiquitination at K798 (P = 0.1296)
MVP		0.53
MPC		0.048
ClinPred		0.072	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.56
Mutation Taster		=42/58	disease causing

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: rs369449324; hg19: chr9-377154;