10-127447420-G-C

Variant names:

• chr10-127447420-G-C
• rs869801
• NM_001290223.2:c.5440G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001290223.2(DOCK1):​c.5440G>C​(p.Ala1814Pro) variant causes a missense 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1814V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOCK1 NM_001290223.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.848
• Publications: 30 publications found

Genes affected

DOCK1 (HGNC:2987): (dedicator of cytokinesis 1) This gene encodes a member of the dedicator of cytokinesis protein family. Dedicator of cytokinesis proteins act as guanine nucleotide exchange factors for small Rho family G proteins. The encoded protein regulates the small GTPase Rac, thereby influencing several biological processes, including phagocytosis and cell migration. Overexpression of this gene has also been associated with certain cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

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=0.0411911).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290223.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK1	NM_001290223.2	MANE Select	c.5440G>C	p.Ala1814Pro	missense	Exon 51 of 52	NP_001277152.2
	DOCK1	NM_001377543.1		c.5539G>C	p.Ala1847Pro	missense	Exon 52 of 53	NP_001364472.1
	DOCK1	NM_001377544.1		c.5413G>C	p.Ala1805Pro	missense	Exon 52 of 53	NP_001364473.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK1	ENST00000623213.2	TSL:1 MANE Select	c.5440G>C	p.Ala1814Pro	missense	Exon 51 of 52	ENSP00000485033.1
	DOCK1	ENST00000280333.9	TSL:1	c.5377G>C	p.Ala1793Pro	missense	Exon 51 of 52	ENSP00000280333.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 20797

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.33
DANN	Benign	0.88
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.85
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.098
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.075
MutPred		0.20		Loss of catalytic residue at A1793 (P = 0.0578)
MVP		0.40
MPC		0.31
ClinPred		0.058	T
GERP RS		-10
Varity_R		0.054
gMVP		0.093
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs869801; hg19: chr10-129245684;