2-224770222-T-C

Position:

• chr2-224770222-T-C

Variant summary

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

The NM_014689.3(DOCK10):​c.6433A>G​(p.Met2145Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DOCK10 NM_014689.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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

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	Protein	UniProt
DOCK10	NM_014689.3	c.6433A>G	p.Met2145Val	missense_variant	55/56	ENST00000258390.12	NP_055504.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK10	ENST00000258390.12	c.6433A>G	p.Met2145Val	missense_variant	55/56	5	NM_014689.3	ENSP00000258390.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431398 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709316

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: 9.11e-7

Gnomad4 OTH exome AF: 0.00

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

Apr 07, 2022

The c.6433A>G (p.M2145V) alteration is located in exon 55 (coding exon 55) of the DOCK10 gene. This alteration results from a A to G substitution at nucleotide position 6433, causing the methionine (M) at amino acid position 2145 to be replaced by a valine (V). 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	0.45
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.040	.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	.;L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0090	D;D;.
Sift4G	Benign	0.15	T;T;.
Polyphen		0.043	.;B;.
Vest4		0.78
MutPred		0.45		.;Loss of helix (P = 0.0626);.;
MVP		0.33
MPC		0.16
ClinPred		0.81	D
GERP RS		5.4
Varity_R		0.64
gMVP		0.54

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: chr2-225634939;