rs2303296

Positions:

• chr2-24209970-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006277.3(ITSN2):​c.4321T>C​(p.Leu1441=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,613,620 control chromosomes in the GnomAD database, including 50,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3122 hom., cov: 31)
  • Exomes 𝑓: 0.25 (46965 hom.)
• Consequence: ITSN2 NM_006277.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0520

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-24209970-A-G is Benign according to our data. Variant chr2-24209970-A-G is described in ClinVar as [Benign]. Clinvar id is 1251753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITSN2	NM_006277.3	c.4321T>C	p.Leu1441=	synonymous_variant	35/40	ENST00000355123.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITSN2	ENST00000355123.9	c.4321T>C	p.Leu1441=	synonymous_variant	35/40	1	NM_006277.3	P2
ITSN2	ENST00000361999.7	c.4240T>C	p.Leu1414=	synonymous_variant	34/39	1		A2
ITSN2	ENST00000479575.1	n.360T>C		non_coding_transcript_exon_variant	1/4	5
ITSN2	ENST00000427234.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27360 AN: 152044 Hom.: 3121 Cov.: 31

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.200 AC: 50268 AN: 251492 Hom.: 5675 AF XY: 0.206 AC XY: 28014 AN XY: 135920

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.190

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.246 AC: 360241 AN: 1461456 Hom.: 46965 Cov.: 34 AF XY: 0.246 AC XY: 178544 AN XY: 727048

Gnomad4 AFR exome AF: 0.0503

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.180 AC: 27355 AN: 152164 Hom.: 3122 Cov.: 31 AF XY: 0.177 AC XY: 13137 AN XY: 74394

Gnomad4 AFR AF: 0.0553

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.176

Alfa AF: 0.239 Hom.: 6774

Bravo AF: 0.172

Asia WGS AF: 0.141 AC: 492 AN: 3478

EpiCase AF: 0.256

EpiControl AF: 0.255

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ITSN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2303296; hg19: chr2-24432839;