2-24208315-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006277.3(ITSN2):c.4600G>A(p.Ala1534Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,610,200 control chromosomes in the GnomAD database, including 48,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (3036 hom., cov: 31)
  • Exomes 𝑓: 0.24 (45220 hom.)
• Consequence: ITSN2 NM_006277.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022797585).
• BP6: Variant 2-24208315-C-T is Benign according to our data. Variant chr2-24208315-C-T is described in ClinVar as [Benign]. Clinvar id is 1240643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITSN2	NM_006277.3	c.4600G>A	p.Ala1534Thr	missense_variant	37/40	ENST00000355123.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITSN2	ENST00000355123.9	c.4600G>A	p.Ala1534Thr	missense_variant	37/40	1	NM_006277.3	P2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 26950 AN: 151830 Hom.: 3035 Cov.: 31

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.197 AC: 49356 AN: 250018 Hom.: 5485 AF XY: 0.204 AC XY: 27532 AN XY: 135218

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.187

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.242 AC: 352831 AN: 1458250 Hom.: 45220 Cov.: 32 AF XY: 0.241 AC XY: 174973 AN XY: 725616

Gnomad4 AFR exome AF: 0.0500

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.265

Gnomad4 OTH exome AF: 0.227

GnomAD4 genome AF: 0.177 AC: 26949 AN: 151950 Hom.: 3036 Cov.: 31 AF XY: 0.174 AC XY: 12945 AN XY: 74256

Gnomad4 AFR AF: 0.0548

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.176

Alfa AF: 0.229 Hom.: 6761

Bravo AF: 0.170

TwinsUK AF: 0.268 AC: 993

ALSPAC AF: 0.269 AC: 1037

ESP6500AA AF: 0.0592 AC: 261

ESP6500EA AF: 0.242 AC: 2084

ExAC AF: 0.196 AC: 23826

Asia WGS AF: 0.139 AC: 487 AN: 3478

EpiCase AF: 0.252

EpiControl AF: 0.251

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

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.5e-7	P;P;P
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.5	N;N;.
REVEL	Benign	0.20
Sift	Benign	0.16	T;T;.
Sift4G	Benign	0.22	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.35
MPC		0.14
ClinPred		0.020	T
GERP RS		4.9
Varity_R		0.10
gMVP		0.49

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: rs2303291; hg19: chr2-24431184; COSMIC: COSV61943586; COSMIC: COSV61943586;