Genetic Variant DOCK9:p.Glu1898Lys (chr13-98805032-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001366683.2(DOCK9):c.5692G>A(p.Glu1898Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000333 in 1,609,944 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 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

DOCK9
NM_001366683.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

Publications

2 publications found

Variant links:

Genes affected

DOCK9 (HGNC:14132): (dedicator of cytokinesis 9) Enables cadherin binding activity. Predicted to be involved in positive regulation of GTPase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

DOCK9 Gene-Disease associations (from GenCC):

keratoconus
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DOCK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.079199195).

BS2

High AC in GnomAd4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366683.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK9	NM_001366683.2	MANE Select	c.5692G>A	p.Glu1898Lys	missense	Exon 49 of 53	NP_001353612.1	A0A804HIE8
DOCK9	NM_001366681.2		c.5797G>A	p.Glu1933Lys	missense	Exon 51 of 55	NP_001353610.1
DOCK9	NM_001366684.2		c.5761G>A	p.Glu1921Lys	missense	Exon 50 of 54	NP_001353613.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK9	ENST00000682017.1	MANE Select	c.5692G>A	p.Glu1898Lys	missense	Exon 49 of 53	ENSP00000507034.1	A0A804HIE8
DOCK9	ENST00000903387.1		c.5692G>A	p.Glu1898Lys	missense	Exon 50 of 54	ENSP00000573446.1
DOCK9	ENST00000448493.7	TSL:5	c.5659G>A	p.Glu1887Lys	missense	Exon 49 of 53	ENSP00000401958.4	A0A088AWN3

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000382

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000360

AC:

AN:

241942

AF XY:

0.000336

show subpopulations

Gnomad AFR exome

AF:

0.0000681

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000474

Gnomad NFE exome

AF:

0.000757

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.000349

AC:

509

AN:

1457654

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

252

AN XY:

724606

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.00

AC:

AN:

85212

European-Finnish (FIN)

AF:

0.0000754

AC:

AN:

53084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000444

AC:

493

AN:

1110178

Other (OTH)

AF:

0.000183

AC:

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000177

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000465

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000598

AC:

ExAC

AF:

0.000480

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.018

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.36

PhyloP100

5.9

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.20

Sift

Benign

0.045

Sift4G

Uncertain

0.044

Polyphen

0.10

Vest4

0.53

MVP

0.51

MPC

0.57

ClinPred

0.20

GERP RS

5.4

gMVP

0.61

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over