1-113829592-C-G

Position:

chr1-113829592-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

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

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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 submissions are: {Uncertain_significance=2, Benign=1}. Variant chr1-113829592-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PTPN22	NM_015967.8 linkuse as main transcript	c.2250G>C	p.Lys750Asn	missense_variant, splice_region_variant	18/21	ENST00000359785.10
PTPN22	XM_047417630.1 linkuse as main transcript	c.2100G>C	p.Lys700Asn	missense_variant, splice_region_variant	16/19
AP4B1-AS1	NR_125965.1 linkuse as main transcript	n.414+14120C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN22	ENST00000359785.10 linkuse as main transcript	c.2250G>C	p.Lys750Asn	missense_variant, splice_region_variant	18/21	1	NM_015967.8	P1
	ENST00000664434.1 linkuse as main transcript	n.419-2170C>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.00581

AC:

1388

AN:

238860

Hom.:

AF XY:

0.00578

AC XY:

750

AN XY:

129702

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 SAS exome

AF:

0.00370

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

Gnomad4 AFR exome

AF:

0.000667

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00511

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00381

Gnomad4 FIN exome

AF:

0.0208

Gnomad4 NFE exome

AF:

0.00645

Gnomad4 OTH exome

AF:

0.00549

GnomAD4 genome

AF:

0.00575

AC:

871

AN:

151384

Hom.:

Cov.:

AF XY:

0.00628

AC XY:

464

AN XY:

73914

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.00132

Gnomad4 ASJ

AF:

0.00722

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0243

Gnomad4 NFE

AF:

0.00748

Gnomad4 OTH

AF:

0.00142

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

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PTPN22: PP3, BS1, BS2 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 11, 2015

- -

PTPN22-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2024

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

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over