Genetic Variant DOK6:p.Leu21Phe (chr18-69401305-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152721.6(DOK6):c.61C>T(p.Leu21Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000261 in 1,573,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

DOK6
NM_152721.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06739211).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152721.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK6	NM_152721.6	MANE Select	c.61C>T	p.Leu21Phe	missense	Exon 1 of 8	NP_689934.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK6	ENST00000382713.10	TSL:1 MANE Select	c.61C>T	p.Leu21Phe	missense	Exon 1 of 8	ENSP00000372160.5	Q6PKX4
	DOK6	ENST00000893242.1		c.61C>T	p.Leu21Phe	missense	Exon 1 of 7	ENSP00000563301.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000762

AC:

AN:

196950

AF XY:

0.0000653

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00155

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000231

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1421712

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

705980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30808

American (AMR)

AF:

0.00

AC:

AN:

40594

Ashkenazi Jewish (ASJ)

AF:

0.00105

AC:

AN:

24774

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35606

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00000458

AC:

AN:

1092518

Other (OTH)

AF:

0.0000684

AC:

AN:

58508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000414

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.0094

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

Eigen

Benign

-0.066

Eigen_PC

Benign

0.035

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.4

PhyloP100

3.7

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.71

REVEL

Uncertain

0.34

Sift

Benign

0.54

Sift4G

Uncertain

0.053

Polyphen

0.18

Vest4

0.35

MutPred

0.56

Gain of methylation at K20 (P = 0.0395)

MVP

0.74

MPC

0.45

ClinPred

0.22

GERP RS

4.1

PromoterAI

0.059

Neutral

(source)

Varity_R

0.19

gMVP

0.29

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over