rs187220094

Variant names:

• chr5-169882683-G-A
• rs187220094
• NM_001129891.3:c.1216C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-169882683-G-A
• chr5-169882683-G-C
• chr5-169882683-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001129891.3(INSYN2B):​c.1216C>T​(p.Arg406Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,552,032 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: INSYN2B NM_001129891.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.07
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008737147).
• BP6: Variant 5-169882683-G-A is Benign according to our data. Variant chr5-169882683-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2656065.
• BS2: High Homozygotes in GnomAd4 at 2 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.1216C>T	p.Arg406Trp	missense	Exon 2 of 4	NP_001123363.1	A6NMK8
	DOCK2	NM_004946.3	MANE Select	c.2799+41831G>A		intron	N/A	NP_004937.1	Q92608-1
	INSYN2B	NM_001346304.2		c.1216C>T	p.Arg406Trp	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.1216C>T	p.Arg406Trp	missense	Exon 2 of 4	ENSP00000366582.3	A6NMK8
	DOCK2	ENST00000520908.7	TSL:2 MANE Select	c.2799+41831G>A		intron	N/A	ENSP00000429283.3	Q92608-1
	DOCK2	ENST00000524185.5	TSL:1	n.2799+41831G>A		intron	N/A	ENSP00000428850.1	E5RFJ0

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152114 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00177 AC: 280 AN: 158242 AF XY: 0.00179

Gnomad AFR exome AF: 0.000241

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.000586

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000589

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00271 AC: 3792 AN: 1399800 Hom.: 9 Cov.: 32 AF XY: 0.00259 AC XY: 1786 AN XY: 690384

African (AFR) AF: 0.000506 AC: 16 AN: 31598

American (AMR) AF: 0.00230 AC: 82 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.000874 AC: 22 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.000505 AC: 40 AN: 79236

European-Finnish (FIN) AF: 0.000586 AC: 29 AN: 49478

Middle Eastern (MID) AF: 0.00193 AC: 11 AN: 5698

European-Non Finnish (NFE) AF: 0.00320 AC: 3448 AN: 1079024

Other (OTH) AF: 0.00248 AC: 144 AN: 58138

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152232 Hom.: 2 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74428

African (AFR) AF: 0.000578 AC: 24 AN: 41532

American (AMR) AF: 0.00255 AC: 39 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 68020

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00275 Hom.: 2

Bravo AF: 0.00218

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00285 AC: 11

ExAC AF: 0.00137 AC: 35

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.1
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.061
Sift	Benign	0.076	T
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.091
MVP		0.49
ClinPred		0.020	T
GERP RS		1.1
Varity_R		0.031
gMVP		0.34
Mutation Taster		=98/2	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: rs187220094; hg19: chr5-169309687; COSMIC: COSV56969681; COSMIC: COSV56969681;