18-69739083-G-C

Variant summary

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

The NM_152721.6(DOK6):c.718G>C(p.Glu240Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOK6 NM_152721.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK6	NM_152721.6	c.718G>C	p.Glu240Gln	missense_variant	6/8	ENST00000382713.10
DOK6	XM_017025610.2	c.394G>C	p.Glu132Gln	missense_variant	4/6
DOK6	XM_017025611.2	c.394G>C	p.Glu132Gln	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK6	ENST00000382713.10	c.718G>C	p.Glu240Gln	missense_variant	6/8	1	NM_152721.6	P1
DOK6	ENST00000582992.1	c.430G>C	p.Glu144Gln	missense_variant	3/3	3
DOK6	ENST00000577609.1	n.99G>C		non_coding_transcript_exon_variant	1/4	3
DOK6	ENST00000584435.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Feb 07, 2023

The c.718G>C (p.E240Q) alteration is located in exon 6 (coding exon 6) of the DOK6 gene. This alteration results from a G to C substitution at nucleotide position 718, causing the glutamic acid (E) at amino acid position 240 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	0.16
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.44
Sift	Benign	0.39	T
Sift4G	Benign	0.30	T
Polyphen		0.96	D
Vest4		0.49
MutPred		0.27		Gain of MoRF binding (P = 0.0528);
MVP		0.93
MPC		0.99
ClinPred		0.80	D
GERP RS		6.1
Varity_R		0.20
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-67406319;