1-113829659-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000359785.10(PTPN22):c.2183C>T(p.Thr728Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,608,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PTPN22
ENST00000359785.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.611

Publications

1 publications found

Variant links:

Genes affected

PTPN22 (HGNC:9652): (protein tyrosine phosphatase non-receptor type 22) This gene encodes of member of the non-receptor class 4 subfamily of the protein-tyrosine phosphatase family. The encoded protein is a lymphoid-specific intracellular phosphatase that associates with the molecular adapter protein CBL and may be involved in regulating CBL function in the T-cell receptor signaling pathway. Mutations in this gene may be associated with a range of autoimmune disorders including Type 1 Diabetes, rheumatoid arthritis, systemic lupus erythematosus and Graves' disease. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Mar 2009]

PTPN22 links:

AP4B1-AS1 (HGNC:44114): (AP4B1 antisense RNA 1)

AP4B1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12391576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
PTPN22	NM_015967.8 link	c.2183C>T	p.Thr728Ile	missense_variant	Exon 18 of 21	NP_057051.4	Q9Y2R2B4DZW8
PTPN22	NM_001308297.2 link	c.2111C>T	p.Thr704Ile	missense_variant	Exon 17 of 20	NP_001295226.2	Q9Y2R2G3K0T4
PTPN22	NM_001193431.3 link	c.2099C>T	p.Thr700Ile	missense_variant	Exon 18 of 21	NP_001180360.2	Q9Y2R2-4B4DZW8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN22	ENST00000359785.10 link	c.2183C>T	p.Thr728Ile	missense_variant	Exon 18 of 21	1		ENSP00000352833.5		A0A0B4J1S7

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248918

AF XY:

0.0000223

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000618

AC:

AN:

1457340

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33180

American (AMR)

AF:

0.00

AC:

AN:

44084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.000105

AC:

AN:

85914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110136

Other (OTH)

AF:

0.00

AC:

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150934

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73578

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41062

American (AMR)

AF:

0.00

AC:

AN:

15102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000417

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67794

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Diabetes mellitus type 1

Uncertain:1

Apr 24, 2025

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variant in exon 18 of the PTPN22 gene that results in an amino acid substitution of Isoleucine for Threonine at codon 728 was detected. The observed variant c.2183C>T (p.Thr728Ile) has not been reported in the 1000 genomes but has a MAF of 0.0006% in the gnomAD databases. The in-silico prediction of the variant is disease causing by MutationTaster2. In summary, the variant meets our criteria to be classified as the variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

.;.;T;.;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.041

FATHMM_MKL

Benign

0.049

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.12

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.61

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.5

D;.;D;D;D

REVEL

Benign

0.070

Sift

Uncertain

0.0040

D;.;D;D;D

Sift4G

Uncertain

0.036

D;T;T;D;D

Polyphen

0.97

.;.;.;D;.

Vest4

0.19

MutPred

0.11

Loss of glycosylation at T728 (P = 0.0421);.;.;Loss of glycosylation at T728 (P = 0.0421);.;

MVP

0.61

MPC

0.22

ClinPred

0.46

GERP RS

2.1

gMVP

0.17

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

1-113829659-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over