rs56048322

chr1-113829592-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

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:1 B:1
• Conservation: PhyloP100: 1.95

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]

(HGNC:):

ACMG classification

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: {Benign=1, Uncertain_significance=1}. Variant chr1-113829592-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN22	NM_015967.8	c.2250G>C	p.Lys750Asn	missense_variant, splice_region_variant	18/21	ENST00000359785.10
PTPN22	XM_047417630.1	c.2100G>C	p.Lys700Asn	missense_variant, splice_region_variant	16/19
AP4B1-AS1	NR_125965.1	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	c.2250G>C	p.Lys750Asn	missense_variant, splice_region_variant	18/21	1	NM_015967.8	P1
	ENST00000664434.1	n.419-2170C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 871 AN: 151272 Hom.: 9 Cov.: 32

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.: 9 AF XY: 0.00578 AC XY: 750 AN XY: 129702

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.: 52 Cov.: 27 AF XY: 0.00617 AC XY: 4346 AN XY: 703932

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.: 9 Cov.: 32 AF XY: 0.00628 AC XY: 464 AN XY: 73914

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.: 4

Bravo AF: 0.00381

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00530 AC: 643

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

PTPN22: PP3, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
MetaRNN	Benign	0.0074	T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.44	T
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	T
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

Other links and lift over

dbSNP: rs56048322; hg19: chr1-114372214; COSMIC: COSV100703307; COSMIC: COSV100703307;