rs1469763130

Variant names:

• chr20-54643458-C-G
• rs1469763130
• NM_018431.5:c.736C>G

Your query was ambiguous. Multiple possible variants found:

• chr20-54643458-C-G
• chr20-54643458-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018431.5(DOK5):​c.736C>G​(p.Leu246Val) variant causes a missense, splice region 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. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOK5 NM_018431.5 missense, splice_region
• Scores: Splicing: ADA: 0.4499
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32

Genes affected

DOK5 (HGNC:16173): (docking protein 5) The protein encoded by this gene is a member of the DOK family of membrane proteins, which are adapter proteins involved in signal transduction. The encoded protein interacts with phosphorylated receptor tyrosine kinases to mediate neurite outgrowth and activation of the MAP kinase pathway. Unlike other DOK family proteins, this protein does not interact with RASGAP. This protein is up-regulated in patients with systemic sclerosis and is associated with fibrosis induced by insulin-like growth factor binding protein 5. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3644283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK5	NM_018431.5	c.736C>G	p.Leu246Val	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000262593.10	NP_060901.2
DOK5	NM_177959.3	c.412C>G	p.Leu138Val	missense_variant, splice_region_variant	Exon 7 of 8		NP_808874.1
DOK5	XM_024451946.2	c.700C>G	p.Leu234Val	missense_variant, splice_region_variant	Exon 7 of 8		XP_024307714.1
DOK5	XM_011528904.2	c.412C>G	p.Leu138Val	missense_variant, splice_region_variant	Exon 7 of 8		XP_011527206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK5	ENST00000262593.10	c.736C>G	p.Leu246Val	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_018431.5	ENSP00000262593.5
DOK5	ENST00000395939.5	c.412C>G	p.Leu138Val	missense_variant, splice_region_variant	Exon 7 of 8	1		ENSP00000379270.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.88	P;P
Vest4		0.28
MutPred		0.53		Gain of catalytic residue at L246 (P = 0.0448);.;
MVP		0.94
MPC		0.39
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.28
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.45
dbscSNV1_RF	Benign	0.30
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: rs1469763130; hg19: chr20-53259997;