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GeneBe

rs2476601

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000359785.10(PTPN22):c.1858T>C(p.Trp620Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,574,936 control chromosomes in the GnomAD database, including 658,157 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.93 ( 66570 hom., cov: 31)
Exomes 𝑓: 0.91 ( 591587 hom. )

Consequence

PTPN22
ENST00000359785.10 missense

Scores

1
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.807
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=5.5175065E-7).
BP6
Variant 1-113834946-A-G is Benign according to our data. Variant chr1-113834946-A-G is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPN22NM_015967.8 linkuse as main transcriptc.1858T>C p.Trp620Arg missense_variant 14/21 ENST00000359785.10
PTPN22XM_047417630.1 linkuse as main transcriptc.1708T>C p.Trp570Arg missense_variant 12/19
AP4B1-AS1NR_125965.1 linkuse as main transcriptn.414+19474A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN22ENST00000359785.10 linkuse as main transcriptc.1858T>C p.Trp620Arg missense_variant 14/211 NM_015967.8 P1
ENST00000664434.1 linkuse as main transcriptn.470+3133A>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.934
AC:
142065
AN:
152082
Hom.:
66511
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.985
Gnomad AMI
AF:
0.961
Gnomad AMR
AF:
0.961
Gnomad ASJ
AF:
0.944
Gnomad EAS
AF:
1.00
Gnomad SAS
AF:
0.988
Gnomad FIN
AF:
0.853
Gnomad MID
AF:
0.984
Gnomad NFE
AF:
0.900
Gnomad OTH
AF:
0.946
GnomAD3 exomes
AF:
0.929
AC:
203641
AN:
219224
Hom.:
94842
AF XY:
0.930
AC XY:
111378
AN XY:
119762
show subpopulations
Gnomad AFR exome
AF:
0.986
Gnomad AMR exome
AF:
0.969
Gnomad ASJ exome
AF:
0.949
Gnomad EAS exome
AF:
1.00
Gnomad SAS exome
AF:
0.987
Gnomad FIN exome
AF:
0.851
Gnomad NFE exome
AF:
0.901
Gnomad OTH exome
AF:
0.928
GnomAD4 exome
AF:
0.911
AC:
1296378
AN:
1422736
Hom.:
591587
Cov.:
40
AF XY:
0.913
AC XY:
646370
AN XY:
707954
show subpopulations
Gnomad4 AFR exome
AF:
0.987
Gnomad4 AMR exome
AF:
0.967
Gnomad4 ASJ exome
AF:
0.952
Gnomad4 EAS exome
AF:
1.00
Gnomad4 SAS exome
AF:
0.985
Gnomad4 FIN exome
AF:
0.855
Gnomad4 NFE exome
AF:
0.899
Gnomad4 OTH exome
AF:
0.928
GnomAD4 genome
AF:
0.934
AC:
142183
AN:
152200
Hom.:
66570
Cov.:
31
AF XY:
0.935
AC XY:
69589
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.985
Gnomad4 AMR
AF:
0.961
Gnomad4 ASJ
AF:
0.944
Gnomad4 EAS
AF:
1.00
Gnomad4 SAS
AF:
0.987
Gnomad4 FIN
AF:
0.853
Gnomad4 NFE
AF:
0.900
Gnomad4 OTH
AF:
0.946
Alfa
AF:
0.915
Hom.:
140296
Bravo
AF:
0.944
TwinsUK
AF:
0.897
AC:
3327
ALSPAC
AF:
0.899
AC:
3465
ESP6500AA
AF:
0.982
AC:
4326
ESP6500EA
AF:
0.906
AC:
7791
ExAC
AF:
0.933
AC:
113294

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.020
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.53
Cadd
Benign
16
Dann
Benign
0.84
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.023
N
LIST_S2
Benign
0.025
T;T;T;T;T
MetaRNN
Benign
5.5e-7
T;T;T;T;T
MetaSVM
Benign
-0.91
T
MutationTaster
Benign
1.0
P;P;P;P;P;P
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
5.1
N;.;N;N;N
REVEL
Benign
0.063
Sift
Benign
1.0
T;.;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.0
.;.;.;B;.
Vest4
0.13
MutPred
0.37
Gain of disorder (P = 6e-04);.;.;Gain of disorder (P = 6e-04);.;
MPC
0.13
ClinPred
0.0017
T
GERP RS
2.7
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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.

Other links and lift over

dbSNP: rs2476601; hg19: chr1-114377568; API