Variant 10-127175327-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039762.3(INSYN2A):c.1069G>A(p.Asp357Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

INSYN2A
NM_001039762.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.46

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSYN2A	NM_001039762.3 linkuse as main transcript	c.1069G>A	p.Asp357Asn	missense_variant	4/6	ENST00000522781.6
DOCK1	NM_001290223.2 linkuse as main transcript	c.2847+47563C>T		intron_variant		ENST00000623213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSYN2A	ENST00000522781.6 linkuse as main transcript	c.1069G>A	p.Asp357Asn	missense_variant	4/6	2	NM_001039762.3	P1	Q6ZSG2-1
DOCK1	ENST00000623213.2 linkuse as main transcript	c.2847+47563C>T		intron_variant		1	NM_001290223.2

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251466

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000575

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000218

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

Jan 04, 2022

The c.1069G>A (p.D357N) alteration is located in exon 4 (coding exon 1) of the FAM196A gene. This alteration results from a G to A substitution at nucleotide position 1069, causing the aspartic acid (D) at amino acid position 357 to be replaced by an asparagine (N). 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

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;.

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.68

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

Sift4G

Benign

0.12

T;T;T

Polyphen

1.0

.;D;.

Vest4

0.56

MVP

0.12

MPC

0.57

ClinPred

0.63

GERP RS

5.1

Varity_R

0.40

gMVP

0.59

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