NM_001129891.3:c.1089C>T

Variant names:

• chr5-169882810-G-A
• rs115307165
• NM_001129891.3:c.1089C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001129891.3(INSYN2B):​c.1089C>T​(p.Thr363Thr) 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
• Publications: 0 publications found

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]

DOCK2 Gene-Disease associations (from GenCC):

• DOCK2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001129891.3. 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
	INSYN2B	NM_001129891.3	MANE Select	c.1089C>T	p.Thr363Thr	synonymous	Exon 2 of 4	NP_001123363.1	A6NMK8
	DOCK2	NM_004946.3	MANE Select	c.2799+41958G>A		intron	N/A	NP_004937.1	Q92608-1
	INSYN2B	NM_001346304.2		c.1089C>T	p.Thr363Thr	synonymous	Exon 2 of 4	NP_001333233.1	A6NMK8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSYN2B	ENST00000377365.4	TSL:2 MANE Select	c.1089C>T	p.Thr363Thr	synonymous	Exon 2 of 4	ENSP00000366582.3	A6NMK8
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.2799+41958G>A		intron	N/A	ENSP00000429283.3	Q92608-1
	DOCK2	ENST00000524185.5	TSL:1	n.2799+41958G>A		intron	N/A	ENSP00000428850.1	E5RFJ0

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

GnomAD2 exomes AF: 0.00470 AC: 738 AN: 156982 AF XY: 0.00531

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 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

African (AFR) AF: 0.000538 AC: 17 AN: 31590

American (AMR) AF: 0.00160 AC: 57 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.0394 AC: 991 AN: 25176

East Asian (EAS) AF: 0.000616 AC: 22 AN: 35724

South Asian (SAS) AF: 0.00875 AC: 693 AN: 79228

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49330

Middle Eastern (MID) AF: 0.00755 AC: 43 AN: 5694

European-Non Finnish (NFE) AF: 0.00116 AC: 1250 AN: 1078710

Other (OTH) AF: 0.00491 AC: 285 AN: 58036

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

African (AFR) AF: 0.000409 AC: 17 AN: 41534

American (AMR) AF: 0.00216 AC: 33 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00813 AC: 39 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 67998

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00411 Hom.: 3

Bravo AF: 0.00246

Asia WGS AF: 0.00231 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.73
PhyloP100		0.039
Mutation Taster		=100/0	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: rs115307165; hg19: chr5-169309814;