2-24203719-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_006277.3(ITSN2):c.5001T>C(p.Pro1667=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,614,202 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (3 hom.)
• Consequence: ITSN2 NM_006277.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.51

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-24203719-A-G is Benign according to our data. Variant chr2-24203719-A-G is described in ClinVar as [Benign]. Clinvar id is 3039372.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITSN2	NM_006277.3	c.5001T>C	p.Pro1667=	synonymous_variant	40/40	ENST00000355123.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITSN2	ENST00000355123.9	c.5001T>C	p.Pro1667=	synonymous_variant	40/40	1	NM_006277.3	P2
ITSN2	ENST00000361999.7	c.4920T>C	p.Pro1640=	synonymous_variant	39/39	1		A2
ITSN2	ENST00000478720.1	n.1180T>C		non_coding_transcript_exon_variant	2/2	2
ITSN2	ENST00000427234.5	c.*370T>C		3_prime_UTR_variant, NMD_transcript_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000927 AC: 233 AN: 251448 Hom.: 2 AF XY: 0.000589 AC XY: 80 AN XY: 135912

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000578

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: 0.0000791

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000358 AC: 524 AN: 1461866 Hom.: 3 Cov.: 31 AF XY: 0.000300 AC XY: 218 AN XY: 727230

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00364 AC: 555 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74500

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00188 Hom.: 0

Bravo AF: 0.00401

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ITSN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.34
Dann	Benign	0.53

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: rs144802071; hg19: chr2-24426588;