Variant 10-127175537-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039762.3(INSYN2A):c.859G>C(p.Glu287Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00013 in 1,610,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

INSYN2A
NM_001039762.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44

Variant links:

Genes affected

INSYN2A (HGNC:33859): (inhibitory synaptic factor 2A) Predicted to be involved in inhibitory postsynaptic potential. Predicted to be active in postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

INSYN2A links:

DOCK1 (HGNC:2987): (dedicator of cytokinesis 1) This gene encodes a member of the dedicator of cytokinesis protein family. Dedicator of cytokinesis proteins act as guanine nucleotide exchange factors for small Rho family G proteins. The encoded protein regulates the small GTPase Rac, thereby influencing several biological processes, including phagocytosis and cell migration. Overexpression of this gene has also been associated with certain cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

DOCK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14557078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSYN2A	NM_001039762.3 linkuse as main transcript	c.859G>C	p.Glu287Gln	missense_variant	4/6	ENST00000522781.6
DOCK1	NM_001290223.2 linkuse as main transcript	c.2847+47773C>G		intron_variant		ENST00000623213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSYN2A	ENST00000522781.6 linkuse as main transcript	c.859G>C	p.Glu287Gln	missense_variant	4/6	2	NM_001039762.3	P1	Q6ZSG2-1
DOCK1	ENST00000623213.2 linkuse as main transcript	c.2847+47773C>G		intron_variant		1	NM_001290223.2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000446

AC:

AN:

246404

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

133880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1458340

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

725624

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000174

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000723

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.859G>C (p.E287Q) alteration is located in exon 4 (coding exon 1) of the FAM196A gene. This alteration results from a G to C substitution at nucleotide position 859, causing the glutamic acid (E) at amino acid position 287 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.59

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;T;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

Sift4G

Benign

0.22

T;T;T

Polyphen

0.35

.;B;.

Vest4

0.17

MVP

0.093

MPC

0.18

ClinPred

0.16

GERP RS

4.2

Varity_R

0.067

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over