chr18-12801998-G-C

Variant names:

• chr18-12801998-G-C
• rs148776205
• NM_002828.4:c.1012C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002828.4(PTPN2):​c.1012C>G​(p.Gln338Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000285 in 1,608,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q338K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: PTPN2 NM_002828.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.76
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056078047).
• BS2: High AC in GnomAd4 at 32 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002828.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN2	NM_002828.4	MANE Select	c.1012C>G	p.Gln338Glu	missense	Exon 8 of 9	NP_002819.2	P17706-1
	PTPN2	NM_001207013.2		c.1081C>G	p.Gln361Glu	missense	Exon 9 of 11	NP_001193942.1	P17706-4
	PTPN2	NM_080422.3		c.1012C>G	p.Gln338Glu	missense	Exon 8 of 10	NP_536347.1	P17706-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN2	ENST00000309660.10	TSL:1 MANE Select	c.1012C>G	p.Gln338Glu	missense	Exon 8 of 9	ENSP00000311857.3	P17706-1
	PTPN2	ENST00000591115.5	TSL:1	c.1081C>G	p.Gln361Glu	missense	Exon 9 of 11	ENSP00000466936.1	P17706-4
	PTPN2	ENST00000327283.7	TSL:1	c.1012C>G	p.Gln338Glu	missense	Exon 8 of 10	ENSP00000320298.3	P17706-2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000276 AC: 69 AN: 249844 AF XY: 0.000281

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000292 AC: 426 AN: 1456754 Hom.: 0 Cov.: 30 AF XY: 0.000298 AC XY: 216 AN XY: 724450

African (AFR) AF: 0.000120 AC: 4 AN: 33344

American (AMR) AF: 0.0000900 AC: 4 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.000653 AC: 17 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.000141 AC: 12 AN: 85158

European-Finnish (FIN) AF: 0.0000752 AC: 4 AN: 53198

Middle Eastern (MID) AF: 0.000422 AC: 2 AN: 4738

European-Non Finnish (NFE) AF: 0.000333 AC: 370 AN: 1110232

Other (OTH) AF: 0.000216 AC: 13 AN: 60090

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74418

African (AFR) AF: 0.0000482 AC: 2 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.084
Sift	Benign	0.43	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.33
MVP		0.38
MPC		0.095
ClinPred		0.052	T
GERP RS		5.5
PromoterAI		0.10	Neutral
Varity_R		0.10
gMVP		0.17
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs148776205; hg19: chr18-12801997;