18-69739102-G-A

Variant summary

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

The NM_152721.6(DOK6):c.737G>A(p.Arg246Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000328 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DOK6
NM_152721.6 missense, splice_region

Scores

Splicing: ADA: 0.9633

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.00

Variant links:

Genes affected

DOK6 (HGNC:28301): (docking protein 6) DOK6 is a member of the DOK (see DOK1; MIM 602919) family of intracellular adaptors that play a role in the RET (MIM 164761) signaling cascade (Crowder et al., 2004 [PubMed 15286081]).[supplied by OMIM, Mar 2008]

DOK6 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=0.12018877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DOK6	NM_152721.6 linkuse as main transcript	c.737G>A	p.Arg246Gln	missense_variant, splice_region_variant	6/8	ENST00000382713.10
DOK6	XM_017025610.2 linkuse as main transcript	c.413G>A	p.Arg138Gln	missense_variant, splice_region_variant	4/6
DOK6	XM_017025611.2 linkuse as main transcript	c.413G>A	p.Arg138Gln	missense_variant, splice_region_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DOK6	ENST00000382713.10 linkuse as main transcript	c.737G>A	p.Arg246Gln	missense_variant, splice_region_variant	6/8	1	NM_152721.6	P1
DOK6	ENST00000582992.1 linkuse as main transcript	c.449G>A	p.Arg150Gln	missense_variant	3/3	3
DOK6	ENST00000577609.1 linkuse as main transcript	n.118G>A		splice_region_variant, non_coding_transcript_exon_variant	1/4	3
DOK6	ENST00000584435.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152196

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

250892

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000478

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Jan 17, 2024

The c.737G>A (p.R246Q) alteration is located in exon 6 (coding exon 6) of the DOK6 gene. This alteration results from a G to A substitution at nucleotide position 737, causing the arginine (R) at amino acid position 246 to be replaced by a glutamine (Q). 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

0.074

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.074

Eigen

Benign

0.035

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.015

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.83

MutationTaster

Benign

0.99

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.32

Sift

Benign

0.35

Sift4G

Benign

0.32

Polyphen

0.28

Vest4

0.12

MutPred

0.26

Loss of MoRF binding (P = 0.1008);

MVP

0.75

MPC

0.45

ClinPred

0.087

GERP RS

6.1

Varity_R

0.23

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Benign

0.56

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