5-169864459-A-C

Variant names:

• chr5-169864459-A-C
• rs1449991385
• NM_001129891.3:c.1422T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001129891.3(INSYN2B):​c.1422T>G​(p.Ser474Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,374,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S474S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: INSYN2B NM_001129891.3 missense, splice_region
• Scores: Splicing: ADA: 0.03731
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

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.1422T>G	p.Ser474Arg	missense splice_region	Exon 4 of 4	NP_001123363.1	A6NMK8
	DOCK2	NM_004946.3	MANE Select	c.2799+23607A>C		intron	N/A	NP_004937.1	Q92608-1
	INSYN2B	NM_001346304.2		c.1422T>G	p.Ser474Arg	missense splice_region	Exon 4 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.1422T>G	p.Ser474Arg	missense splice_region	Exon 4 of 4	ENSP00000366582.3	A6NMK8
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.2799+23607A>C		intron	N/A	ENSP00000429283.3	Q92608-1
	DOCK2	ENST00000524185.5	TSL:1	n.2799+23607A>C		intron	N/A	ENSP00000428850.1	E5RFJ0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1374050 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 675840

African (AFR) AF: 0.00 AC: 0 AN: 30602

American (AMR) AF: 0.0000618 AC: 2 AN: 32370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23276

East Asian (EAS) AF: 0.00 AC: 0 AN: 35574

South Asian (SAS) AF: 0.00 AC: 0 AN: 74858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067346

Other (OTH) AF: 0.00 AC: 0 AN: 56870

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.36	T
PhyloP100		1.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.44		Gain of sheet (P = 0.1208)
MVP		0.44
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.77
gMVP		0.66
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.037
dbscSNV1_RF	Benign	0.35
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: rs1449991385; hg19: chr5-169291463;