2-24208254-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.53

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]

ACMG classification

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 GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITSN2	NM_006277.3	c.4661G>A	p.Arg1554His	missense_variant	37/40	ENST00000355123.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITSN2	ENST00000355123.9	c.4661G>A	p.Arg1554His	missense_variant	37/40	1	NM_006277.3	P2

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152008 Hom.: 2 Cov.: 31

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.: 6 AF XY: 0.00223 AC XY: 302 AN XY: 135536

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.: 15 Cov.: 31 AF XY: 0.00192 AC XY: 1398 AN XY: 726606

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.: 2 Cov.: 31 AF XY: 0.00333 AC XY: 248 AN XY: 74376

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.: 1

Bravo AF: 0.00131

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ITSN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 16, 2019

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	23
Dann	Uncertain	0.98
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0095	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.74	T
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	T
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

Other links and lift over

dbSNP: rs138517130; hg19: chr2-24431123; COSMIC: COSV61944912; COSMIC: COSV61944912;