5-169883150-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001129891.3(INSYN2B):c.749T>C(p.Leu250Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: INSYN2B NM_001129891.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.98

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049616903).
• BP6: Variant 5-169883150-A-G is Benign according to our data. Variant chr5-169883150-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3110019.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSYN2B	NM_001129891.3	c.749T>C	p.Leu250Pro	missense_variant	2/4	ENST00000377365.4
DOCK2	NM_004946.3	c.2799+42298A>G		intron_variant		ENST00000520908.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSYN2B	ENST00000377365.4	c.749T>C	p.Leu250Pro	missense_variant	2/4	2	NM_001129891.3	P1
DOCK2	ENST00000520908.7	c.2799+42298A>G		intron_variant		2	NM_004946.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399358 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 690192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	14
Dann	Benign	0.81
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.037
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.040
MVP		0.20
ClinPred		0.086	T
GERP RS		2.4
Varity_R		0.053
gMVP		0.11

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: rs1167346897; hg19: chr5-169310154; COSMIC: COSV56971853; COSMIC: COSV56971853;