Genetic Variant PTPN6:p.Cys361* (chr12-6957662-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_002831.6(PTPN6):c.1083C>A(p.Cys361*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000803 in 1,244,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C361C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

PTPN6
NM_002831.6 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.550

Publications

0 publications found

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]

PTPN6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002831.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN6	NM_002831.6	MANE Select	c.1083C>A	p.Cys361*	stop_gained	Exon 10 of 16	NP_002822.2
PTPN6	NM_080549.4		c.1083C>A	p.Cys361*	stop_gained	Exon 10 of 16	NP_536859.1	P29350-4
PTPN6	NM_080548.5		c.1089C>A	p.Cys363*	stop_gained	Exon 10 of 16	NP_536858.1	Q53XS4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN6	ENST00000318974.14	TSL:1 MANE Select	c.1083C>A	p.Cys361*	stop_gained	Exon 10 of 16	ENSP00000326010.9	P29350-1
PTPN6	ENST00000456013.5	TSL:1	c.1083C>A	p.Cys361*	stop_gained	Exon 10 of 16	ENSP00000391592.1	P29350-4
PTPN6	ENST00000399448.5	TSL:1	c.1089C>A	p.Cys363*	stop_gained	Exon 10 of 16	ENSP00000382376.1	P29350-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.03e-7

AC:

AN:

1244644

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

623058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28120

American (AMR)

AF:

0.00

AC:

AN:

41384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21822

East Asian (EAS)

AF:

0.00

AC:

AN:

30724

South Asian (SAS)

AF:

0.00

AC:

AN:

82736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4992

European-Non Finnish (NFE)

AF:

0.00000106

AC:

AN:

943598

Other (OTH)

AF:

0.00

AC:

AN:

49900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.83

PhyloP100

0.55

Vest4

0.97

GERP RS

1.4

Mutation Taster

=1/199

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over