18-12814242-T-C

Variant names:

• chr18-12814242-T-C
• rs2041989064
• NM_002828.4:c.819A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002828.4(PTPN2):​c.819A>G​(p.Ile273Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PTPN2 NM_002828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

Genes affected

PTPN2 (HGNC:9650): (protein tyrosine phosphatase non-receptor type 2) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Members of the PTP family share a highly conserved catalytic motif, which is essential for the catalytic activity. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Epidermal growth factor receptor and the adaptor protein Shc were reported to be substrates of this PTP, which suggested the roles in growth factor mediated cell signaling. Multiple alternatively spliced transcript variants encoding different isoforms have been found. Two highly related but distinctly processed pseudogenes that localize to chromosomes 1 and 13, respectively, have been reported. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN2	NM_002828.4	c.819A>G	p.Ile273Met	missense_variant	Exon 7 of 9	ENST00000309660.10	NP_002819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN2	ENST00000309660.10	c.819A>G	p.Ile273Met	missense_variant	Exon 7 of 9	1	NM_002828.4	ENSP00000311857.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452760 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.819A>G (p.I273M) alteration is located in exon 7 (coding exon 7) of the PTPN2 gene. This alteration results from a A to G substitution at nucleotide position 819, causing the isoleucine (I) at amino acid position 273 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;.;T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	2.0	M;.;M;M;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N;.;N;N;.;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.023	D;.;D;D;.;.;.
Sift4G	Uncertain	0.020	D;D;D;D;D;.;.
Polyphen		0.47	P;.;.;P;.;.;.
Vest4		0.44
MutPred		0.70		Gain of MoRF binding (P = 0.0728);.;Gain of MoRF binding (P = 0.0728);Gain of MoRF binding (P = 0.0728);.;.;.;
MVP		0.62
MPC		0.11
ClinPred		0.86	D
GERP RS		5.9
Varity_R		0.48
gMVP		0.47

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: rs2041989064; hg19: chr18-12814241;