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GeneBe

2-24204298-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006277.3(ITSN2):c.4883A>G(p.Tyr1628Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ITSN2
NM_006277.3 missense

Scores

2
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ITSN2NM_006277.3 linkuse as main transcriptc.4883A>G p.Tyr1628Cys missense_variant 39/40 ENST00000355123.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ITSN2ENST00000355123.9 linkuse as main transcriptc.4883A>G p.Tyr1628Cys missense_variant 39/401 NM_006277.3 P2Q9NZM3-1
ITSN2ENST00000361999.7 linkuse as main transcriptc.4802A>G p.Tyr1601Cys missense_variant 38/391 A2Q9NZM3-2
ITSN2ENST00000478720.1 linkuse as main transcriptn.601A>G non_coding_transcript_exon_variant 2/22
ITSN2ENST00000427234.5 linkuse as main transcriptc.*252A>G 3_prime_UTR_variant, NMD_transcript_variant 4/53

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251490
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000527
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000417
AC:
61
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.0000358
AC XY:
26
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000513
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 11, 2022The c.4883A>G (p.Y1628C) alteration is located in exon 39 (coding exon 38) of the ITSN2 gene. This alteration results from a A to G substitution at nucleotide position 4883, causing the tyrosine (Y) at amino acid position 1628 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Uncertain
-0.060
Cadd
Uncertain
25
Dann
Uncertain
0.99
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Uncertain
0.73
D;D;D
MetaSVM
Benign
-0.52
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.9
D;D;.
REVEL
Uncertain
0.43
Sift
Uncertain
0.025
D;D;.
Sift4G
Benign
0.070
T;T;T
Polyphen
0.94
P;P;.
Vest4
0.74
MVP
0.79
MPC
0.19
ClinPred
0.43
T
GERP RS
5.1
Varity_R
0.21
gMVP
0.40

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs750743467; hg19: chr2-24427167; API