18-12814349-T-C

Variant names:

• chr18-12814349-T-C
• rs778472790
• NM_002828.4:c.712A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002828.4(PTPN2):​c.712A>G​(p.Lys238Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000133 in 1,431,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PTPN2 NM_002828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15196022).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN2	NM_002828.4	c.712A>G	p.Lys238Glu	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.712A>G	p.Lys238Glu	missense_variant	Exon 7 of 9	1	NM_002828.4	ENSP00000311857.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000627 AC: 14 AN: 223424 Hom.: 0 AF XY: 0.0000494 AC XY: 6 AN XY: 121442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000541

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000133 AC: 19 AN: 1431836 Hom.: 0 Cov.: 30 AF XY: 0.0000113 AC XY: 8 AN XY: 710596

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000491

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.712A>G (p.K238E) 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 712, causing the lysine (K) at amino acid position 238 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;.;T;.;.;.
Eigen	Benign	0.040
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.91	L;.;L;L;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D;.;D;D;.;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.044	D;.;T;D;.;.;.
Sift4G	Uncertain	0.057	T;T;T;T;D;.;.
Polyphen		0.11	B;.;.;B;.;.;.
Vest4		0.53
MutPred		0.35		Loss of ubiquitination at K238 (P = 0.0218);.;Loss of ubiquitination at K238 (P = 0.0218);Loss of ubiquitination at K238 (P = 0.0218);.;.;.;
MVP		0.42
MPC		0.30
ClinPred		0.24	T
GERP RS		4.7
Varity_R		0.56
gMVP		0.69

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: rs778472790; hg19: chr18-12814348;