rs114888195

chr5-169702404-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_004946.3(DOCK2):c.1360G>A(p.Ala454Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,613,862 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A454V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: DOCK2 NM_004946.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.02

Genes affected

DOCK2 (HGNC:2988): (dedicator of cytokinesis 2) The protein encoded by this gene belongs to the CDM protein family. It is specifically expressed in hematopoietic cells and is predominantly expressed in peripheral blood leukocytes. The protein is involved in remodeling of the actin cytoskeleton required for lymphocyte migration in response to chemokine signaling. It activates members of the Rho family of GTPases, for example RAC1 and RAC2, by acting as a guanine nucleotide exchange factor (GEF) to exchange bound GDP for free GTP. Mutations in this gene result in immunodeficiency 40 (IMD40), a combined form of immunodeficiency that affects T cell number and function, also with variable defects in B cell and NK cell function. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DOCK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008157015).
• BP6: Variant 5-169702404-G-A is Benign according to our data. Variant chr5-169702404-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475999.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00193 (294/152260) while in subpopulation AFR AF= 0.00676 (281/41544). AF 95% confidence interval is 0.00611. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK2	NM_004946.3	c.1360G>A	p.Ala454Thr	missense_variant	14/52	ENST00000520908.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK2	ENST00000520908.7	c.1360G>A	p.Ala454Thr	missense_variant	14/52	2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000534 AC: 134 AN: 250952 Hom.: 0 AF XY: 0.000428 AC XY: 58 AN XY: 135606

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461602 Hom.: 3 Cov.: 31 AF XY: 0.000238 AC XY: 173 AN XY: 727116

Gnomad4 AFR exome AF: 0.00765

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74438

Gnomad4 AFR AF: 0.00676

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000355 Hom.: 1

Bravo AF: 0.00209

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000626 AC: 76

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

DOCK2 deficiency Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

DOCK2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.1
Dann	Benign	0.93
DEOGEN2	Benign	0.046	T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0082	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N;N;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.96	N;.;.;.
REVEL	Benign	0.063
Sift	Benign	0.19	T;.;.;.
Sift4G	Benign	0.094	T;.;.;T
Polyphen		0.0	B;B;.;.
Vest4		0.057
MVP		0.11
MPC		0.50
ClinPred		0.0078	T
GERP RS		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs114888195; hg19: chr5-169129408;