9-312088-C-G

Position:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_203447.4(DOCK8):​c.663C>G​(p.Asp221Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

Frequency

Genomes: not found (cov: 32)

Consequence

DOCK8
NM_203447.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03537205).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOCK8NM_203447.4 linkc.663C>G p.Asp221Glu missense_variant 6/48 ENST00000432829.7 NP_982272.2 Q8NF50-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOCK8ENST00000432829.7 linkc.663C>G p.Asp221Glu missense_variant 6/481 NM_203447.4 ENSP00000394888.3 Q8NF50-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
15
DANN
Benign
0.26
DEOGEN2
Benign
0.10
T;.;.
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.71
T;T;T
M_CAP
Benign
0.0042
T
MetaRNN
Benign
0.035
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.93
N;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.99
.;N;N
REVEL
Benign
0.065
Sift
Benign
1.0
.;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.16
MutPred
0.20
Gain of helix (P = 0.0225);.;.;
MVP
0.20
MPC
0.042
ClinPred
0.073
T
GERP RS
2.8
Varity_R
0.069
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139391329; hg19: chr9-312088; API