rs2242241

Positions:

• chr8-21909370-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003974.4(DOK2):​c.1180T>G​(p.Ser394Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,582,630 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0083 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (130 hom.)
• Consequence: DOK2 NM_003974.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.190

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021086633).
• BP6: Variant 8-21909370-A-C is Benign according to our data. Variant chr8-21909370-A-C is described in ClinVar as [Benign]. Clinvar id is 771423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK2	NM_003974.4	c.1180T>G	p.Ser394Ala	missense_variant	5/5	ENST00000276420.9	NP_003965.2
DOK2	NM_001401272.1	c.898T>G	p.Ser300Ala	missense_variant	4/4		NP_001388201.1
DOK2	NM_001317800.2	c.718T>G	p.Ser240Ala	missense_variant	3/3		NP_001304729.1
DOK2	NM_201349.3	c.718T>G	p.Ser240Ala	missense_variant	4/4		NP_958728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK2	ENST00000276420.9	c.1180T>G	p.Ser394Ala	missense_variant	5/5	1	NM_003974.4	ENSP00000276420.4

Frequencies

GnomAD3 genomes AF: 0.00826 AC: 1258 AN: 152224 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0730

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00924

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0105 AC: 2369 AN: 225874 Hom.: 93 AF XY: 0.00821 AC XY: 998 AN XY: 121532

Gnomad AFR exome AF: 0.000565

Gnomad AMR exome AF: 0.0663

Gnomad ASJ exome AF: 0.00197

Gnomad EAS exome AF: 0.0110

Gnomad SAS exome AF: 0.000352

Gnomad FIN exome AF: 0.000453

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00280 AC: 4001 AN: 1430288 Hom.: 130 Cov.: 30 AF XY: 0.00248 AC XY: 1758 AN XY: 708486

Gnomad4 AFR exome AF: 0.000522

Gnomad4 AMR exome AF: 0.0667

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.000295

Gnomad4 FIN exome AF: 0.000288

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00827 AC: 1260 AN: 152342 Hom.: 54 Cov.: 32 AF XY: 0.00991 AC XY: 738 AN XY: 74484

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.0730

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00927

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00103 Hom.: 5

Bravo AF: 0.0113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00709 AC: 860

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2019	This variant is associated with the following publications: (PMID: 30206226) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.028
Sift	Benign	0.76	T
Sift4G	Benign	0.45	T
Polyphen		0.028	B
Vest4		0.056
MPC		0.031
ClinPred		0.16	T
GERP RS		1.3
Varity_R		0.034
gMVP		0.081

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

Other links and lift over

dbSNP: rs2242241; hg19: chr8-21766881;