18-12817349-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002828.4(PTPN2):c.512C>A(p.Thr171Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,613,352 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (45 hom.)
• Consequence: PTPN2 NM_002828.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.82

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007090658).
• BP6: Variant 18-12817349-G-T is Benign according to our data. Variant chr18-12817349-G-T is described in ClinVar as [Benign]. Clinvar id is 775462.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2142/152230) while in subpopulation AFR AF= 0.0489 (2031/41524). AF 95% confidence interval is 0.0471. There are 50 homozygotes in gnomad4. There are 1020 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN2	NM_002828.4	c.512C>A	p.Thr171Lys	missense_variant	6/9	ENST00000309660.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN2	ENST00000309660.10	c.512C>A	p.Thr171Lys	missense_variant	6/9	1	NM_002828.4	A1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2136 AN: 152112 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00351 AC: 882 AN: 251118 Hom.: 17 AF XY: 0.00256 AC XY: 347 AN XY: 135760

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00137 AC: 2002 AN: 1461122 Hom.: 45 Cov.: 31 AF XY: 0.00114 AC XY: 829 AN XY: 726946

Gnomad4 AFR exome AF: 0.0494

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.0141 AC: 2142 AN: 152230 Hom.: 50 Cov.: 32 AF XY: 0.0137 AC XY: 1020 AN XY: 74432

Gnomad4 AFR AF: 0.0489

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00294 Hom.: 15

Bravo AF: 0.0160

ESP6500AA AF: 0.0504 AC: 222

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00423 AC: 514

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Benign	0.94
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D;T;D;D;D;.;D
MetaRNN	Benign	0.0071	T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.63	N;.;N;N;.;.;.
MutationTaster	Benign	0.70	N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.41	N;.;N;N;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.22	T;.;T;T;.;.;.
Sift4G	Benign	0.32	T;T;T;T;T;.;.
Polyphen		0.013	B;.;.;B;.;.;.
Vest4		0.25
MVP		0.49
MPC		1.2
ClinPred		0.011	T
GERP RS		3.1
Varity_R		0.12
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: rs78174797; hg19: chr18-12817348;