5-169882810-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001129891.3(INSYN2B):c.1089C>T(p.Thr363=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,551,368 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (34 hom.)
• Consequence: INSYN2B NM_001129891.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0390

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-169882810-G-A is Benign according to our data. Variant chr5-169882810-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 772874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.039 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSYN2B	NM_001129891.3	c.1089C>T	p.Thr363=	synonymous_variant	2/4	ENST00000377365.4
DOCK2	NM_004946.3	c.2799+41958G>A		intron_variant		ENST00000520908.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSYN2B	ENST00000377365.4	c.1089C>T	p.Thr363=	synonymous_variant	2/4	2	NM_001129891.3	P1
DOCK2	ENST00000520908.7	c.2799+41958G>A		intron_variant		2	NM_004946.3	P1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 345 AN: 152068 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00812

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00470 AC: 738 AN: 156982 Hom.: 11 AF XY: 0.00531 AC XY: 441 AN XY: 83046

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0402

Gnomad EAS exome AF: 0.000459

Gnomad SAS exome AF: 0.00891

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00240 AC: 3359 AN: 1399182 Hom.: 34 Cov.: 32 AF XY: 0.00270 AC XY: 1861 AN XY: 690028

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00160

Gnomad4 ASJ exome AF: 0.0394

Gnomad4 EAS exome AF: 0.000616

Gnomad4 SAS exome AF: 0.00875

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.00116

Gnomad4 OTH exome AF: 0.00491

GnomAD4 genome AF: 0.00227 AC: 345 AN: 152186 Hom.: 3 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74398

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00813

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00411 Hom.: 3

Bravo AF: 0.00246

Asia WGS AF: 0.00231 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	INSYN2B: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.1
Dann	Benign	0.73

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: rs115307165; hg19: chr5-169309814;