rs34908836

Variant names:

• chr9-449874-G-C
• rs34908836
• NM_203447.4:c.5908G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-449874-G-C
• chr9-449874-G-A

Variant summary

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

The NM_203447.4(DOCK8):​c.5908G>C​(p.Ala1970Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,613,720 control chromosomes in the GnomAD database, including 3,600 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1970G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.073 (546 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3054 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.62
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001698941).
• BP6: Variant 9-449874-G-C is Benign according to our data. Variant chr9-449874-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

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.5908G>C	p.Ala1970Pro	missense	Exon 45 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.5704G>C	p.Ala1902Pro	missense	Exon 44 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.5608G>C	p.Ala1870Pro	missense	Exon 43 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.5908G>C	p.Ala1970Pro	missense	Exon 45 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.5608G>C	p.Ala1870Pro	missense	Exon 43 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.5608G>C	p.Ala1870Pro	missense	Exon 44 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.0725 AC: 11023 AN: 152122 Hom.: 544 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0417

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0569

GnomAD2 exomes AF: 0.0612 AC: 15389 AN: 251416 AF XY: 0.0658

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.0478

Gnomad EAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0455

Gnomad NFE exome AF: 0.0452

Gnomad OTH exome AF: 0.0561

GnomAD4 exome AF: 0.0531 AC: 77552 AN: 1461480 Hom.: 3054 Cov.: 33 AF XY: 0.0563 AC XY: 40938 AN XY: 727014

African (AFR) AF: 0.140 AC: 4675 AN: 33466

American (AMR) AF: 0.0317 AC: 1418 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 1284 AN: 26134

East Asian (EAS) AF: 0.00625 AC: 248 AN: 39700

South Asian (SAS) AF: 0.160 AC: 13836 AN: 86236

European-Finnish (FIN) AF: 0.0432 AC: 2306 AN: 53414

Middle Eastern (MID) AF: 0.0639 AC: 350 AN: 5478

European-Non Finnish (NFE) AF: 0.0450 AC: 50060 AN: 1111972

Other (OTH) AF: 0.0559 AC: 3375 AN: 60356

GnomAD4 genome AF: 0.0726 AC: 11052 AN: 152240 Hom.: 546 Cov.: 32 AF XY: 0.0746 AC XY: 5553 AN XY: 74444

African (AFR) AF: 0.132 AC: 5503 AN: 41536

American (AMR) AF: 0.0516 AC: 789 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3472

East Asian (EAS) AF: 0.00869 AC: 45 AN: 5176

South Asian (SAS) AF: 0.179 AC: 863 AN: 4826

European-Finnish (FIN) AF: 0.0417 AC: 442 AN: 10606

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3087 AN: 68016

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0498 Hom.: 169

Bravo AF: 0.0713

TwinsUK AF: 0.0423 AC: 157

ALSPAC AF: 0.0397 AC: 153

ESP6500AA AF: 0.133 AC: 584

ESP6500EA AF: 0.0456 AC: 392

ExAC AF: 0.0646 AC: 7842

Asia WGS AF: 0.0930 AC: 324 AN: 3478

EpiCase AF: 0.0529

EpiControl AF: 0.0491

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N
PhyloP100		2.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.13
Sift	Benign	0.60	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.096
MPC		0.054
ClinPred		0.0076	T
GERP RS		3.7
Varity_R		0.23
gMVP		0.64
Mutation Taster		=78/22	polymorphism (auto)

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: rs34908836; hg19: chr9-449874; COSMIC: COSV66620191; COSMIC: COSV66620191;