Genetic Variant ENST00000359785.10:c.2242A>G (chr1-113829600-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000359785.10(PTPN22):c.2242A>G(p.Arg748Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,586,510 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 1 hom. )

Consequence

PTPN22
ENST00000359785.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.92

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:

ENSG00000231128 (HGNC:):

ENSG00000231128 links:

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

AP4B1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047892004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
PTPN22	NM_015967.8 link	c.2242A>G	p.Arg748Gly	missense_variant	Exon 18 of 21	NP_057051.4	Q9Y2R2B4DZW8
PTPN22	NM_001308297.2 link	c.2170A>G	p.Arg724Gly	missense_variant	Exon 17 of 20	NP_001295226.2	Q9Y2R2G3K0T4
PTPN22	NM_001193431.3 link	c.2158A>G	p.Arg720Gly	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.2242A>G	p.Arg748Gly	missense_variant	Exon 18 of 21	1		ENSP00000352833.5		A0A0B4J1S7

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000645

AC:

157

AN:

243374

Hom.:

AF XY:

0.000538

AC XY:

AN XY:

131978

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.000156

Gnomad ASJ exome

AF:

0.00113

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000705

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00102

GnomAD4 exome

AF:

0.000560

AC:

803

AN:

1434290

Hom.:

Cov.:

AF XY:

0.000509

AC XY:

364

AN XY:

714946

show subpopulations

Gnomad4 AFR exome

AF:

0.0000309

Gnomad4 AMR exome

AF:

0.000238

Gnomad4 ASJ exome

AF:

0.00109

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.000722

Gnomad4 NFE exome

AF:

0.000635

Gnomad4 OTH exome

AF:

0.000522

GnomAD4 genome

AF:

0.000414

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.000677

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000565

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000749

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;.;T;.;T

Eigen

Benign

0.031

Eigen_PC

Benign

0.0026

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.048

T;T;T;T;T

MetaSVM

Benign

-0.58

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.7

D;.;D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0050

D;.;D;D;D

Sift4G

Uncertain

0.043

D;D;D;D;D

Polyphen

1.0

.;.;.;D;.

Vest4

0.56

MVP

0.81

MPC

0.48

ClinPred

0.16

GERP RS

4.4

gMVP

0.46

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over