rs146210506

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001367561.1(DOCK7):c.2371C>A(p.Leu791Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,613,698 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 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

DOCK7
NM_001367561.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.08

Publications

0 publications found

Variant links:

Genes affected

DOCK7 (HGNC:19190): (dedicator of cytokinesis 7) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that plays a role in axon formation and neuronal polarization. The encoded protein displays GEF activity toward RAC1 and RAC3 Rho small GTPases but not toward CDC42. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

DOCK7 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 23
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

DOCK7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30349332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK7	NM_001367561.1 link	c.2371C>A	p.Leu791Ile	missense_variant	Exon 20 of 50	ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK7	ENST00000635253.2 link	c.2371C>A	p.Leu791Ile	missense_variant	Exon 20 of 50	5	NM_001367561.1	ENSP00000489124.1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152074

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000837

AC:

AN:

250812

AF XY:

0.0000885

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000205

AC:

299

AN:

1461624

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000234

AC:

260

AN:

1111886

Other (OTH)

AF:

0.000580

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

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:

0.0000921

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.000225

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 23

Uncertain:2

Aug 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 791 of the DOCK7 protein (p.Leu791Ile). This variant is present in population databases (rs146210506, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DOCK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 571504). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2371C>A (p.L791I) alteration is located in exon 20 (coding exon 20) of the DOCK7 gene. This alteration results from a C to A substitution at nucleotide position 2371, causing the leucine (L) at amino acid position 791 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 12, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;.;.;.;.;T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.30

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;L;L;L;L;.

PhyloP100

8.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.58

N;.;N;.;.;.;.

REVEL

Benign

0.15

Sift

Benign

0.18

T;.;T;.;.;.;.

Sift4G

Benign

0.31

T;T;T;T;T;T;.

Polyphen

0.016, 0.71, 0.91

.;B;P;P;P;.;.

Vest4

0.47

MVP

0.42

MPC

0.54

ClinPred

0.16

GERP RS

5.1

Varity_R

0.45

gMVP

0.27

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over