Variant 2-24208290-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_006277.3(ITSN2):c.4625C>T(p.Ala1542Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,610,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

ITSN2
NM_006277.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.33

Variant links:

Genes affected

ITSN2 (HGNC:6184): (intersectin 2) This gene encodes a cytoplasmic protein which contains SH3 domains. This protein is a member of a family of proteins involved in clathrin-mediated endocytosis. Intersectin 2 is thought to regulate the formation of clathrin-coated vesicles and also may function in the induction of T cell antigen receptor (TCR) endocytosis. [provided by RefSeq, Jan 2017]

ITSN2 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
ITSN2	NM_006277.3 linkuse as main transcript	c.4625C>T	p.Ala1542Val	missense_variant	37/40	ENST00000355123.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITSN2	ENST00000355123.9 linkuse as main transcript	c.4625C>T	p.Ala1542Val	missense_variant	37/40	1	NM_006277.3	P2	Q9NZM3-1

Frequencies

GnomAD3 genomes

AF:

0.0000597

AC:

AN:

150780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000426

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000740

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000679

AC:

AN:

250442

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000968

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1460114

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726450

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000597

AC:

AN:

150780

Hom.:

Cov.:

AF XY:

0.0000544

AC XY:

AN XY:

73564

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000426

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000740

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

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

Apr 28, 2022

The c.4625C>T (p.A1542V) alteration is located in exon 37 (coding exon 36) of the ITSN2 gene. This alteration results from a C to T substitution at nucleotide position 4625, causing the alanine (A) at amino acid position 1542 to be replaced by a valine (V). 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

Uncertain

0.51

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Uncertain

0.010

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

0.29

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.1

D;D;.

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.65

MVP

0.92

MPC

0.15

ClinPred

0.65

GERP RS

4.8

Varity_R

0.45

gMVP

0.76

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