9-441952-G-C

Variant names:

• chr9-441952-G-C
• rs1887957
• NM_203447.4:c.5433G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_203447.4(DOCK8):​c.5433G>C​(p.Glu1811Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1811E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5433G>C	p.Glu1811Asp	missense_variant	Exon 42 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.5433G>C	p.Glu1811Asp	missense_variant	Exon 42 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	.;.;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;.;.;D
Vest4		0.47
MutPred		0.42		Loss of catalytic residue at E1811 (P = 0.0537);.;.;.;
MVP		0.36
MPC		0.12
ClinPred		0.96	D
GERP RS		1.7
Varity_R		0.53
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1887957; hg19: chr9-441952;