NM_014689.3:c.6430G>T

Variant names:

• chr2-224770225-C-A
• rs2124944623
• NM_014689.3:c.6430G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014689.3(DOCK10):​c.6430G>T​(p.Val2144Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. V2144I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DOCK10 NM_014689.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• Publications: 0 publications found

Genes affected

DOCK10 (HGNC:23479): (dedicator of cytokinesis 10) This gene encodes a member of the dedicator of cytokinesis protein family. Members of this family are guanosine nucleotide exchange factors for Rho GTPases and defined by the presence of conserved DOCK-homology regions. The encoded protein belongs to the D (or Zizimin) subfamily of DOCK proteins, which also contain an N-terminal pleckstrin homology domain. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Mar 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.108585685).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014689.3. 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
	DOCK10	NM_014689.3	MANE Select	c.6430G>T	p.Val2144Phe	missense	Exon 55 of 56	NP_055504.2	Q96BY6-1
	DOCK10	NM_001363762.1		c.6469G>T	p.Val2157Phe	missense	Exon 55 of 56	NP_001350691.1	A0A2R8YD85
	DOCK10	NM_001290263.2		c.6412G>T	p.Val2138Phe	missense	Exon 55 of 56	NP_001277192.1	Q96BY6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK10	ENST00000258390.12	TSL:5 MANE Select	c.6430G>T	p.Val2144Phe	missense	Exon 55 of 56	ENSP00000258390.7	Q96BY6-1
	DOCK10	ENST00000409592.7	TSL:1	c.6412G>T	p.Val2138Phe	missense	Exon 55 of 56	ENSP00000386694.3	Q96BY6-3
	DOCK10	ENST00000645028.1		c.6469G>T	p.Val2157Phe	missense	Exon 55 of 56	ENSP00000493664.1	A0A2R8YD85

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439968 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714524

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32810

American (AMR) AF: 0.00 AC: 0 AN: 41408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.00 AC: 0 AN: 81964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102002

Other (OTH) AF: 0.00 AC: 0 AN: 59566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.065	N
PhyloP100		0.22
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.023	B
Vest4		0.37
MutPred		0.57		Loss of helix (P = 0.0626)
MVP		0.16
MPC		0.33
ClinPred		0.24	T
GERP RS		-3.8
Varity_R		0.46
gMVP		0.41
Mutation Taster		=87/13	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: rs2124944623; hg19: chr2-225634942;