dbSNP rs33996649: PTPN22:p.Arg263Gln (chr1-113852067-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015967.8(PTPN22):c.788G>A(p.Arg263Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0209 in 1,610,848 control chromosomes in the GnomAD database, including 418 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R263W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 30 hom., cov: 32)

Exomes 𝑓: 0.021 ( 388 hom. )

Consequence

PTPN22
NM_015967.8 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.93

Publications

101 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004177779).

BP6

Variant 1-113852067-C-T is Benign according to our data. Variant chr1-113852067-C-T is described in ClinVar as Benign. ClinVar VariationId is 3353083.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0162 (2469/152216) while in subpopulation NFE AF = 0.0246 (1672/68006). AF 95% confidence interval is 0.0236. There are 30 homozygotes in GnomAd4. There are 1159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015967.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN22	NM_015967.8	MANE Select	c.788G>A	p.Arg263Gln	missense	Exon 10 of 21	NP_057051.4
PTPN22	NM_001308297.2		c.716G>A	p.Arg239Gln	missense	Exon 9 of 20	NP_001295226.2	F5H2S8
PTPN22	NM_001193431.3		c.788G>A	p.Arg263Gln	missense	Exon 10 of 21	NP_001180360.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN22	ENST00000359785.10	TSL:1 MANE Select	c.788G>A	p.Arg263Gln	missense	Exon 10 of 21	ENSP00000352833.5	A0A0B4J1S7
PTPN22	ENST00000420377.6	TSL:1	c.788G>A	p.Arg263Gln	missense	Exon 10 of 20	ENSP00000388229.2	E9PMT0
PTPN22	ENST00000538253.5	TSL:1	c.716G>A	p.Arg239Gln	missense	Exon 9 of 20	ENSP00000439372.2	F5H2S8

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2471

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00488

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0199

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0197

GnomAD2 exomes

AF:

0.0171

AC:

4281

AN:

250966

AF XY:

0.0176

show subpopulations

Gnomad AFR exome

AF:

0.00475

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0223

Gnomad NFE exome

AF:

0.0226

Gnomad OTH exome

AF:

0.0183

GnomAD4 exome

AF:

0.0213

AC:

31131

AN:

1458632

Hom.:

388

Cov.:

AF XY:

0.0209

AC XY:

15178

AN XY:

725736

show subpopulations

African (AFR)

AF:

0.00383

AC:

128

AN:

33422

American (AMR)

AF:

0.0147

AC:

656

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0131

AC:

343

AN:

26096

East Asian (EAS)

AF:

0.000101

AC:

AN:

39656

South Asian (SAS)

AF:

0.0120

AC:

1036

AN:

86106

European-Finnish (FIN)

AF:

0.0196

AC:

1046

AN:

53346

Middle Eastern (MID)

AF:

0.00902

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0241

AC:

26775

AN:

1109272

Other (OTH)

AF:

0.0181

AC:

1091

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

1381

2761

4142

5522

6903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

986

1972

2958

3944

4930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0162

AC:

2469

AN:

152216

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1159

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00486

AC:

202

AN:

41544

American (AMR)

AF:

0.0160

AC:

244

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00994

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0199

AC:

211

AN:

10580

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0246

AC:

1672

AN:

68006

Other (OTH)

AF:

0.0194

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0211

Hom.:

126

Bravo

AF:

0.0151

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.0210

AC:

181

ExAC

AF:

0.0169

AC:

2049

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0228

EpiControl

AF:

0.0211

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

PTPN22-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.047

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.97

PhyloP100

3.9

PrimateAI

Benign

0.38

PROVEAN

Benign

2.6

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.17

MPC

0.083

ClinPred

0.0090

GERP RS

3.4

gMVP

0.12

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over