18-69677735-G-C

Variant summary

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

The NM_152721.6(DOK6):c.291G>C(p.Glu97Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,461,064 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DOK6 NM_152721.6 missense, splice_region
• Scores: Splicing: ADA: 0.06397
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04

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.291G>C	p.Glu97Asp	missense_variant, splice_region_variant	4/8	ENST00000382713.10
DOK6	XM_017025610.2	c.-34G>C		splice_region_variant, 5_prime_UTR_variant	2/6
DOK6	XM_017025611.2	c.-34G>C		splice_region_variant, 5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK6	ENST00000382713.10	c.291G>C	p.Glu97Asp	missense_variant, splice_region_variant	4/8	1	NM_152721.6	P1
DOK6	ENST00000582992.1	c.3G>C	p.Ter1=	coding_sequence_variant	1/3	3
DOK6	ENST00000582172.5	n.262G>C		splice_region_variant, non_coding_transcript_exon_variant	3/4	3
DOK6	ENST00000584435.1	n.105G>C		splice_region_variant, non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461064 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 21, 2023

The c.291G>C (p.E97D) alteration is located in exon 4 (coding exon 4) of the DOK6 gene. This alteration results from a G to C substitution at nucleotide position 291, causing the glutamic acid (E) at amino acid position 97 to be replaced by an aspartic acid (D). 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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.30
Sift	Benign	0.38	T
Sift4G	Benign	0.28	T
Polyphen		0.18	B
Vest4		0.72
MutPred		0.50		Loss of disorder (P = 0.1182);
MVP		0.75
MPC		0.41
ClinPred		0.83	D
GERP RS		4.5
Varity_R		0.17
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.064
dbscSNV1_RF	Benign	0.34
SpliceAI score (max)		0.010		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: rs1388092360; hg19: chr18-67344971;