rs1365961316

Variant names:

• chr5-169882901-C-G
• rs1365961316
• NM_001129891.3:c.998G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001129891.3(INSYN2B):​c.998G>C​(p.Ser333Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INSYN2B NM_001129891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.840
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056598604).

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.998G>C	p.Ser333Thr	missense	Exon 2 of 4	NP_001123363.1	A6NMK8
	DOCK2	NM_004946.3	MANE Select	c.2799+42049C>G		intron	N/A	NP_004937.1	Q92608-1
	INSYN2B	NM_001346304.2		c.998G>C	p.Ser333Thr	missense	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.998G>C	p.Ser333Thr	missense	Exon 2 of 4	ENSP00000366582.3	A6NMK8
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.2799+42049C>G		intron	N/A	ENSP00000429283.3	Q92608-1
	DOCK2	ENST00000524185.5	TSL:1	n.2799+42049C>G		intron	N/A	ENSP00000428850.1	E5RFJ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399646 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 690284

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078932

Other (OTH) AF: 0.00 AC: 0 AN: 58132

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.1
DANN	Benign	0.56
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.84
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.016
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.39	T
Polyphen		0.0070	B
Vest4		0.063
MutPred		0.12		Gain of glycosylation at S333 (P = 0.0289)
MVP		0.061
ClinPred		0.095	T
GERP RS		3.2
Varity_R		0.088
gMVP		0.15
Mutation Taster		=96/4	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: rs1365961316; hg19: chr5-169309905;