rs74163663

chr1-113829600-T-Cchr1-113829600-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92

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 -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/exons	MANE	UniProt
PTPN22	NM_015967.8	c.2242A>G	p.Arg748Gly	missense_variant	18/21	ENST00000359785.10
PTPN22	XM_047417630.1	c.2092A>G	p.Arg698Gly	missense_variant	16/19
AP4B1-AS1	NR_125965.1	n.414+14128T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN22	ENST00000359785.10	c.2242A>G	p.Arg748Gly	missense_variant	18/21	1	NM_015967.8	P1
	ENST00000664434.1	n.419-2162T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152102 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000538 AC XY: 71 AN XY: 131978

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.: 1 Cov.: 28 AF XY: 0.000509 AC XY: 364 AN XY: 714946

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: 63 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74442

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.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000749 AC: 91

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	T
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.031
Eigen_PC	Benign	0.0026
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.048	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.46	T
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	T
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

Other links and lift over

dbSNP: rs74163663; hg19: chr1-114372222;