Genetic Variant ITSN2:p.Arg1554His (chr2-24208254-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006277.3(ITSN2):c.4661G>A(p.Arg1554His) variant causes a missense change. The variant allele was found at a frequency of 0.002 in 1,612,586 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 15 hom. )

Consequence

ITSN2
NM_006277.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.53

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009541094).

BP6

Variant 2-24208254-C-T is Benign according to our data. Variant chr2-24208254-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1176087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITSN2	NM_006277.3 link	c.4661G>A	p.Arg1554His	missense_variant	Exon 37 of 40	ENST00000355123.9	NP_006268.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITSN2	ENST00000355123.9 link	c.4661G>A	p.Arg1554His	missense_variant	Exon 37 of 40	1	NM_006277.3	ENSP00000347244.4		Q9NZM3-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00175

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00227

AC:

569

AN:

250654

Hom.:

AF XY:

0.00223

AC XY:

302

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000926

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00194

AC:

2838

AN:

1460460

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

1398

AN XY:

726606

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.00329

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00104

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.00166

Gnomad4 OTH exome

AF:

0.00219

GnomAD4 genome

AF:

0.00250

AC:

380

AN:

152126

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0162

Gnomad4 NFE

AF:

0.00175

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00176

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ITSN2-related disorder

Benign:1

Sep 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

.;T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0095

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;L;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.3

D;D;.

REVEL

Benign

0.071

Sift

Benign

0.050

D;T;.

Sift4G

Benign

0.084

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.60

MVP

0.75

MPC

0.19

ClinPred

0.031

GERP RS

4.8

Varity_R

0.070

gMVP

0.31

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