20-54610495-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018431.5(DOK5):​c.707G>T​(p.Arg236Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000455 in 1,539,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

DOK5
NM_018431.5 missense

Scores

14
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86
Variant links:
Genes affected
DOK5 (HGNC:16173): (docking protein 5) The protein encoded by this gene is a member of the DOK family of membrane proteins, which are adapter proteins involved in signal transduction. The encoded protein interacts with phosphorylated receptor tyrosine kinases to mediate neurite outgrowth and activation of the MAP kinase pathway. Unlike other DOK family proteins, this protein does not interact with RASGAP. This protein is up-regulated in patients with systemic sclerosis and is associated with fibrosis induced by insulin-like growth factor binding protein 5. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jun 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38964498).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOK5NM_018431.5 linkc.707G>T p.Arg236Leu missense_variant 6/8 ENST00000262593.10 NP_060901.2 Q9P104-1
DOK5NM_177959.3 linkc.383G>T p.Arg128Leu missense_variant 6/8 NP_808874.1 Q9P104-2
DOK5XM_024451946.2 linkc.671G>T p.Arg224Leu missense_variant 6/8 XP_024307714.1
DOK5XM_011528904.2 linkc.383G>T p.Arg128Leu missense_variant 6/8 XP_011527206.1 Q9P104-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOK5ENST00000262593.10 linkc.707G>T p.Arg236Leu missense_variant 6/81 NM_018431.5 ENSP00000262593.5 Q9P104-1
DOK5ENST00000395939.5 linkc.383G>T p.Arg128Leu missense_variant 6/81 ENSP00000379270.1 Q9P104-2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000145
AC:
3
AN:
206968
Hom.:
0
AF XY:
0.0000266
AC XY:
3
AN XY:
112992
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000929
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000991
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000216
AC:
3
AN:
1387360
Hom.:
0
Cov.:
30
AF XY:
0.00000291
AC XY:
2
AN XY:
686438
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000620
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.31e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152234
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 07, 2024The c.707G>T (p.R236L) alteration is located in exon 6 (coding exon 6) of the DOK5 gene. This alteration results from a G to T substitution at nucleotide position 707, causing the arginine (R) at amino acid position 236 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Uncertain
0.060
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.39
T;T
MetaSVM
Uncertain
-0.075
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-2.7
D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0060
D;D
Sift4G
Uncertain
0.012
D;D
Polyphen
0.18
B;P
Vest4
0.50
MutPred
0.44
Loss of MoRF binding (P = 0.0085);.;
MVP
0.92
MPC
1.1
ClinPred
0.83
D
GERP RS
4.8
Varity_R
0.34
gMVP
0.55

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

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

Other links and lift over

dbSNP: rs149752614; hg19: chr20-53227034; API