chr8-21909682-G-T

Position:

• chr8-21909682-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003974.4(DOK2):​c.868C>A​(p.Pro290Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOK2 NM_003974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.996

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 (HGNC:):

ACMG classification

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=0.0761303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK2	NM_003974.4	c.868C>A	p.Pro290Thr	missense_variant	5/5	ENST00000276420.9	NP_003965.2
DOK2	NM_001401272.1	c.586C>A	p.Pro196Thr	missense_variant	4/4		NP_001388201.1
DOK2	NM_001317800.2	c.406C>A	p.Pro136Thr	missense_variant	3/3		NP_001304729.1
DOK2	NM_201349.3	c.406C>A	p.Pro136Thr	missense_variant	4/4		NP_958728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK2	ENST00000276420.9	c.868C>A	p.Pro290Thr	missense_variant	5/5	1	NM_003974.4	ENSP00000276420.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.868C>A (p.P290T) alteration is located in exon 5 (coding exon 5) of the DOK2 gene. This alteration results from a C to A substitution at nucleotide position 868, causing the proline (P) at amino acid position 290 to be replaced by a threonine (T). 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	0.063
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.3
DANN	Benign	0.68
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.80	N;N
REVEL	Benign	0.14
Sift	Benign	0.31	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0	B;.
Vest4		0.045
MutPred		0.27		Gain of phosphorylation at P290 (P = 0.005);.;
MVP		0.29
MPC		0.036
ClinPred		0.11	T
GERP RS		-1.7
Varity_R		0.040
gMVP		0.33

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: rs1809750943; hg19: chr8-21767193;