Variant chr8-21909375-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003974.4(DOK2):c.1175C>G(p.Ser392Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 1,587,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

DOK2
NM_003974.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32

Variant links:

Genes affected

DOK2 (HGNC:2991): (docking protein 2) The protein encoded by this gene is constitutively tyrosine phosphorylated in hematopoietic progenitors isolated from chronic myelogenous leukemia (CML) patients in the chronic phase. It may be a critical substrate for p210(bcr/abl), a chimeric protein whose presence is associated with CML. This encoded protein binds p120 (RasGAP) from CML cells. [provided by RefSeq, Jul 2008]

DOK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.224991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK2	NM_003974.4 linkuse as main transcript	c.1175C>G	p.Ser392Cys	missense_variant	5/5	ENST00000276420.9	NP_003965.2	O60496
DOK2	NM_001401272.1 linkuse as main transcript	c.893C>G	p.Ser298Cys	missense_variant	4/4		NP_001388201.1
DOK2	NM_001317800.2 linkuse as main transcript	c.713C>G	p.Ser238Cys	missense_variant	3/3		NP_001304729.1
DOK2	NM_201349.3 linkuse as main transcript	c.713C>G	p.Ser238Cys	missense_variant	4/4		NP_958728.1	B4DKQ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK2	ENST00000276420.9 linkuse as main transcript	c.1175C>G	p.Ser392Cys	missense_variant	5/5	1	NM_003974.4	ENSP00000276420.4		O60496

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000627

AC:

AN:

1435196

Hom.:

Cov.:

AF XY:

0.00000703

AC XY:

AN XY:

711448

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000819

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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 submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1175C>G (p.S392C) alteration is located in exon 5 (coding exon 5) of the DOK2 gene. This alteration results from a C to G substitution at nucleotide position 1175, causing the serine (S) at amino acid position 392 to be replaced by a cysteine (C). 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

0.082

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.34

Eigen

Benign

-0.012

Eigen_PC

Benign

-0.051

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.58

M_CAP

Benign

0.018

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.7

REVEL

Benign

0.034

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.052

Polyphen

0.85

Vest4

0.17

MutPred

0.27

Loss of disorder (P = 0.0126);

MVP

0.59

MPC

0.035

ClinPred

0.60

GERP RS

5.3

Varity_R

0.13

gMVP

0.26

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