5-169882683-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001129891.3(INSYN2B):c.1216C>T(p.Arg406Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,552,032 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: INSYN2B NM_001129891.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07

Genes affected

INSYN2B (HGNC:37271): (inhibitory synaptic factor family member 2B)

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008737147).
• BP6: Variant 5-169882683-G-A is Benign according to our data. Variant chr5-169882683-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2656065.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSYN2B	NM_001129891.3	c.1216C>T	p.Arg406Trp	missense_variant	2/4	ENST00000377365.4
DOCK2	NM_004946.3	c.2799+41831G>A		intron_variant		ENST00000520908.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSYN2B	ENST00000377365.4	c.1216C>T	p.Arg406Trp	missense_variant	2/4	2	NM_001129891.3	P1
DOCK2	ENST00000520908.7	c.2799+41831G>A		intron_variant		2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152114 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00177 AC: 280 AN: 158242 Hom.: 3 AF XY: 0.00179 AC XY: 149 AN XY: 83396

Gnomad AFR exome AF: 0.000241

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.000586

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000615

Gnomad FIN exome AF: 0.000589

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00271 AC: 3792 AN: 1399800 Hom.: 9 Cov.: 32 AF XY: 0.00259 AC XY: 1786 AN XY: 690384

Gnomad4 AFR exome AF: 0.000506

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.000874

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000505

Gnomad4 FIN exome AF: 0.000586

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152232 Hom.: 2 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74428

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00269 Hom.: 1

Bravo AF: 0.00218

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00285 AC: 11

ExAC AF: 0.00137 AC: 35

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

DOCK2: BS2; INSYN2B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.061
Sift	Benign	0.076	T
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.091
MVP		0.49
ClinPred		0.020	T
GERP RS		1.1
Varity_R		0.031
gMVP		0.34

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: rs187220094; hg19: chr5-169309687; COSMIC: COSV56969681; COSMIC: COSV56969681;