2-24203682-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006277.3(ITSN2):​c.5038G>A​(p.Gly1680Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ITSN2
NM_006277.3 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.55
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ITSN2NM_006277.3 linkc.5038G>A p.Gly1680Arg missense_variant 40/40 ENST00000355123.9 NP_006268.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ITSN2ENST00000355123.9 linkc.5038G>A p.Gly1680Arg missense_variant 40/401 NM_006277.3 ENSP00000347244.4 Q9NZM3-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251390
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1461878
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
19
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152292
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

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 GeneticsJul 25, 2024The c.5038G>A (p.G1680R) alteration is located in exon 40 (coding exon 39) of the ITSN2 gene. This alteration results from a G to A substitution at nucleotide position 5038, causing the glycine (G) at amino acid position 1680 to be replaced by an arginine (R). 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
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
.;D;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.79
D;D;D
MetaSVM
Uncertain
0.32
D
MutationAssessor
Uncertain
2.7
.;M;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-6.2
D;D;.
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0010
D;D;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.85
MutPred
0.71
.;Gain of phosphorylation at T1679 (P = 0.1335);.;
MVP
0.94
MPC
0.18
ClinPred
0.93
D
GERP RS
5.5
Varity_R
0.91
gMVP
0.86

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

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

Other links and lift over

dbSNP: rs200311995; hg19: chr2-24426551; API