9-390512-C-T

Variant names:

• chr9-390512-C-T
• rs2297075
• NM_203447.4:c.2916C>T
• DOCK8 p.Thr972Thr

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.2916C>T​(p.Thr972Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,613,320 control chromosomes in the GnomAD database, including 49,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T972T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5892 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43983 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -1.31
• Publications: 18 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: Orphanet, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 9-390512-C-T is Benign according to our data. Variant chr9-390512-C-T is described in ClinVar as Benign. ClinVar VariationId is 137141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.363 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.2916C>T	p.Thr972Thr	synonymous	Exon 24 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.2712C>T	p.Thr904Thr	synonymous	Exon 23 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.2616C>T	p.Thr872Thr	synonymous	Exon 22 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.2916C>T	p.Thr972Thr	synonymous	Exon 24 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.2616C>T	p.Thr872Thr	synonymous	Exon 22 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.2616C>T	p.Thr872Thr	synonymous	Exon 23 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40843 AN: 151964 Hom.: 5886 Cov.: 32

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.0846

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.228 AC: 57399 AN: 251444 AF XY: 0.230

Gnomad AFR exome AF: 0.368

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.0741

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.241 AC: 351989 AN: 1461238 Hom.: 43983 Cov.: 35 AF XY: 0.241 AC XY: 175559 AN XY: 726970

African (AFR) AF: 0.381 AC: 12761 AN: 33454

American (AMR) AF: 0.211 AC: 9419 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 5254 AN: 26134

East Asian (EAS) AF: 0.0817 AC: 3245 AN: 39700

South Asian (SAS) AF: 0.256 AC: 22062 AN: 86240

European-Finnish (FIN) AF: 0.191 AC: 10180 AN: 53420

Middle Eastern (MID) AF: 0.269 AC: 1553 AN: 5764

European-Non Finnish (NFE) AF: 0.245 AC: 272680 AN: 1111436

Other (OTH) AF: 0.246 AC: 14835 AN: 60370

GnomAD4 genome AF: 0.269 AC: 40864 AN: 152082 Hom.: 5892 Cov.: 32 AF XY: 0.263 AC XY: 19571 AN XY: 74328

African (AFR) AF: 0.367 AC: 15233 AN: 41456

American (AMR) AF: 0.246 AC: 3758 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3470

East Asian (EAS) AF: 0.0848 AC: 440 AN: 5190

South Asian (SAS) AF: 0.251 AC: 1209 AN: 4812

European-Finnish (FIN) AF: 0.191 AC: 2024 AN: 10590

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16602 AN: 67972

Other (OTH) AF: 0.266 AC: 560 AN: 2106

Alfa AF: 0.243 Hom.: 10556

Bravo AF: 0.276

Asia WGS AF: 0.174 AC: 609 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Combined immunodeficiency due to DOCK8 deficiency (2)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2297075;

hg19: chr9-390512;

COSMIC: COSV66619469;