rs2242241

Variant names:

• chr8-21909370-A-C
• rs2242241
• NM_003974.4:c.1180T>G

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003974.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK2	NM_003974.4	MANE Select	c.1180T>G	p.Ser394Ala	missense	Exon 5 of 5	NP_003965.2
	DOK2	NM_001401272.1		c.898T>G	p.Ser300Ala	missense	Exon 4 of 4	NP_001388201.1
	DOK2	NM_001317800.2		c.718T>G	p.Ser240Ala	missense	Exon 3 of 3	NP_001304729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK2	ENST00000276420.9	TSL:1 MANE Select	c.1180T>G	p.Ser394Ala	missense	Exon 5 of 5	ENSP00000276420.4
	DOK2	ENST00000517422.5	TSL:2	n.*720T>G		downstream_gene	N/A	ENSP00000429508.1
	DOK2	ENST00000524001.1	TSL:2	n.*94T>G		downstream_gene	N/A

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

GnomAD2 exomes AF: 0.0105 AC: 2369 AN: 225874 AF XY: 0.00821

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 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

African (AFR) AF: 0.000522 AC: 17 AN: 32566

American (AMR) AF: 0.0667 AC: 2727 AN: 40880

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 31 AN: 23408

East Asian (EAS) AF: 0.0218 AC: 859 AN: 39440

South Asian (SAS) AF: 0.000295 AC: 24 AN: 81410

European-Finnish (FIN) AF: 0.000288 AC: 15 AN: 52118

Middle Eastern (MID) AF: 0.000714 AC: 4 AN: 5606

European-Non Finnish (NFE) AF: 0.000137 AC: 150 AN: 1096004

Other (OTH) AF: 0.00296 AC: 174 AN: 58856

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

African (AFR) AF: 0.000914 AC: 38 AN: 41584

American (AMR) AF: 0.0730 AC: 1118 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00927 AC: 48 AN: 5180

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68028

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00206 Hom.: 8

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

Mar 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30206226)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.19
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2242241; hg19: chr8-21766881;