1-113829592-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_StrongBP6BS2

The ENST00000359785.10(PTPN22):c.2250G>C(p.Lys750Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,561,324 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0058 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 52 hom. )

Consequence

PTPN22
ENST00000359785.10 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.95

Publications

20 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: Likely_benign. The variant received -1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 1-113829592-C-G is Benign according to our data. Variant chr1-113829592-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218728.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High Homozygotes in GnomAd4 at 9 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
PTPN22	NM_015967.8 link	c.2250G>C	p.Lys750Asn	missense_variant, splice_region_variant	Exon 18 of 21	NP_057051.4	Q9Y2R2B4DZW8
PTPN22	NM_001308297.2 link	c.2178G>C	p.Lys726Asn	missense_variant, splice_region_variant	Exon 17 of 20	NP_001295226.2	Q9Y2R2G3K0T4
PTPN22	NM_001193431.3 link	c.2166G>C	p.Lys722Asn	missense_variant, splice_region_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.2250G>C	p.Lys750Asn	missense_variant, splice_region_variant	Exon 18 of 21	1		ENSP00000352833.5		A0A0B4J1S7

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

871

AN:

151272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00722

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0243

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00747

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00581

AC:

1388

AN:

238860

AF XY:

0.00578

show subpopulations

Gnomad AFR exome

AF:

0.000945

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0233

Gnomad NFE exome

AF:

0.00596

Gnomad OTH exome

AF:

0.00591

GnomAD4 exome

AF:

0.00629

AC:

8866

AN:

1409940

Hom.:

Cov.:

AF XY:

0.00617

AC XY:

4346

AN XY:

703932

show subpopulations

African (AFR)

AF:

0.000667

AC:

AN:

31496

American (AMR)

AF:

0.00116

AC:

AN:

40366

Ashkenazi Jewish (ASJ)

AF:

0.00511

AC:

129

AN:

25254

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39190

South Asian (SAS)

AF:

0.00381

AC:

315

AN:

82676

European-Finnish (FIN)

AF:

0.0208

AC:

1091

AN:

52374

Middle Eastern (MID)

AF:

0.00182

AC:

AN:

5492

European-Non Finnish (NFE)

AF:

0.00645

AC:

6931

AN:

1074626

Other (OTH)

AF:

0.00549

AC:

321

AN:

58466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

402

804

1206

1608

2010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00575

AC:

871

AN:

151384

Hom.:

Cov.:

AF XY:

0.00628

AC XY:

464

AN XY:

73914

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

41362

American (AMR)

AF:

0.00132

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00722

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00290

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0243

AC:

248

AN:

10222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00748

AC:

507

AN:

67822

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00630

Hom.:

Bravo

AF:

0.00381

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00530

AC:

643

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTPN22: PP3, BS1, BS2 -

not specified

Uncertain:1

Jun 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PTPN22-related disorder

Benign:1

Aug 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.037

.;.;T;.;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D;D;D;D

MetaRNN

Benign

0.0074

T;T;T;T;T

MetaSVM

Benign

-0.57

PhyloP100

1.9

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.6

D;.;D;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0020

D;.;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D

Polyphen

0.99

.;.;.;D;.

Vest4

0.41

MutPred

0.14

Loss of methylation at K750 (P = 0.039);.;.;Loss of methylation at K750 (P = 0.039);.;

MVP

0.84

MPC

0.44

ClinPred

0.022

GERP RS

5.5

gMVP

0.33

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.91

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-113829592-C-G

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