Genetic Variant DOCK5:p.Glu42Lys (chr8-25243754-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_024940.8(DOCK5):c.124G>A(p.Glu42Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DOCK5
NM_024940.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.96

Variant links:

Genes affected

DOCK5 (HGNC:23476): (dedicator of cytokinesis 5) This gene encodes a member of the dedicator of cytokinesis protein family. Members of this family act as guanine nucleotide exchange factors for small Rho family G proteins. The protein encoded by this gene is thought to associate with adaptors CRK and CRKL, and function in regulation of intestinal epithelial cell spreading and migration on collagen IV. Similar proteins in mouse and zebrafish also function in myoblast fusion. [provided by RefSeq, Oct 2016]

DOCK5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
DOCK5	NM_024940.8 link	c.124G>A	p.Glu42Lys	missense_variant	Exon 2 of 52	ENST00000276440.12	NP_079216.4	Q9H7D0-1Q68DL4
DOCK5	NM_001322810.2 link	c.124G>A	p.Glu42Lys	missense_variant	Exon 2 of 4		NP_001309739.1	B9A015

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DOCK5	ENST00000276440.12 link	c.124G>A	p.Glu42Lys	missense_variant	Exon 2 of 52	1	NM_024940.8	ENSP00000276440.7	Q9H7D0-1
DOCK5	ENST00000481100.5 link	c.124G>A	p.Glu42Lys	missense_variant	Exon 2 of 11	1		ENSP00000429737.1	Q9H7D0-2
DOCK5	ENST00000410074.5 link	c.124G>A	p.Glu42Lys	missense_variant	Exon 2 of 4	2		ENSP00000387036.1	B9A015

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250404

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461152

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726836

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124G>A (p.E42K) alteration is located in exon 2 (coding exon 2) of the DOCK5 gene. This alteration results from a G to A substitution at nucleotide position 124, causing the glutamic acid (E) at amino acid position 42 to be replaced by a lysine (K). 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

0.30

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.051

T;.;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.0096

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

.;L;L

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.8

D;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.019

D;T;T

Sift4G

Uncertain

0.013

D;T;T

Polyphen

0.66

.;.;P

Vest4

0.81

MutPred

0.62

Gain of MoRF binding (P = 0.0053);Gain of MoRF binding (P = 0.0053);Gain of MoRF binding (P = 0.0053);

MVP

0.59

MPC

0.29

ClinPred

0.93

GERP RS

6.2

Varity_R

0.21

gMVP

0.71

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over