12-6952116-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002831.6(PTPN6):​c.265C>T​(p.Arg89Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

PTPN6
NM_002831.6 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.39
Variant links:
Genes affected
PTPN6 (HGNC:9658): (protein tyrosine phosphatase non-receptor type 6) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. N-terminal part of this PTP contains two tandem Src homolog (SH2) domains, which act as protein phospho-tyrosine binding domains, and mediate the interaction of this PTP with its substrates. This PTP is expressed primarily in hematopoietic cells, and functions as an important regulator of multiple signaling pathways in hematopoietic cells. This PTP has been shown to interact with, and dephosphorylate a wide spectrum of phospho-proteins involved in hematopoietic cell signaling. Multiple alternatively spliced variants of this gene, which encode distinct isoforms, have been reported. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPN6NM_002831.6 linkuse as main transcriptc.265C>T p.Arg89Cys missense_variant 3/16 ENST00000318974.14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN6ENST00000318974.14 linkuse as main transcriptc.265C>T p.Arg89Cys missense_variant 3/161 NM_002831.6 P1P29350-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249656
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135380
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461880
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727238
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 24, 2023The c.265C>T (p.R89C) alteration is located in exon 3 (coding exon 3) of the PTPN6 gene. This alteration results from a C to T substitution at nucleotide position 265, causing the arginine (R) at amino acid position 89 to be replaced by a cysteine (C). 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
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.069
T;.;.;D;.;.;T
Eigen
Uncertain
0.24
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.66
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Uncertain
0.70
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.6
.;.;.;M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-5.2
D;D;D;D;D;D;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0010
D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D
Polyphen
0.99
.;.;.;D;.;.;.
Vest4
0.48, 0.36, 0.31
MutPred
0.46
.;.;Loss of disorder (P = 0.0354);Loss of disorder (P = 0.0354);Loss of disorder (P = 0.0354);Loss of disorder (P = 0.0354);.;
MVP
0.78
MPC
2.1
ClinPred
0.99
D
GERP RS
3.7
Varity_R
0.61
gMVP
0.55

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs782163170; hg19: chr12-7061279; COSMIC: COSV59685517; API