Genetic Variant PTPN6:c.1673+22T>C (chr12-6960457-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002831.6(PTPN6):c.1673+22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,606,846 control chromosomes in the GnomAD database, including 599,355 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.79 ( 48561 hom., cov: 33)

Exomes 𝑓: 0.87 ( 550794 hom. )

Consequence

PTPN6
NM_002831.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.42

Publications

14 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
PTPN6	NM_002831.6	MANE Select	c.1673+22T>C	intron	N/A	NP_002822.2
PTPN6	NM_080549.4		c.1673+22T>C	intron	N/A	NP_536859.1	P29350-4
PTPN6	NM_080548.5		c.1679+22T>C	intron	N/A	NP_536858.1	Q53XS4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PTPN6	ENST00000318974.14	TSL:1 MANE Select	c.1673+22T>C	intron	N/A	ENSP00000326010.9	P29350-1
PTPN6	ENST00000456013.5	TSL:1	c.1673+22T>C	intron	N/A	ENSP00000391592.1	P29350-4
PTPN6	ENST00000399448.5	TSL:1	c.1679+22T>C	intron	N/A	ENSP00000382376.1	P29350-3

Frequencies

GnomAD3 genomes

AF:

0.787

AC:

119636

AN:

152022

Hom.:

48551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.565

Gnomad AMI

AF:

0.872

Gnomad AMR

AF:

0.856

Gnomad ASJ

AF:

0.907

Gnomad EAS

AF:

0.856

Gnomad SAS

AF:

0.887

Gnomad FIN

AF:

0.867

Gnomad MID

AF:

0.829

Gnomad NFE

AF:

0.874

Gnomad OTH

AF:

0.813

GnomAD2 exomes

AF:

0.858

AC:

211313

AN:

246382

AF XY:

0.863

show subpopulations

Gnomad AFR exome

AF:

0.555

Gnomad AMR exome

AF:

0.883

Gnomad ASJ exome

AF:

0.902

Gnomad EAS exome

AF:

0.856

Gnomad FIN exome

AF:

0.862

Gnomad NFE exome

AF:

0.879

Gnomad OTH exome

AF:

0.858

GnomAD4 exome

AF:

0.868

AC:

1263368

AN:

1454706

Hom.:

550794

Cov.:

AF XY:

0.870

AC XY:

629833

AN XY:

724046

show subpopulations

African (AFR)

AF:

0.550

AC:

18320

AN:

33322

American (AMR)

AF:

0.878

AC:

39167

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.904

AC:

23593

AN:

26100

East Asian (EAS)

AF:

0.818

AC:

32405

AN:

39626

South Asian (SAS)

AF:

0.884

AC:

76094

AN:

86066

European-Finnish (FIN)

AF:

0.859

AC:

45293

AN:

52712

Middle Eastern (MID)

AF:

0.840

AC:

4821

AN:

5742

European-Non Finnish (NFE)

AF:

0.879

AC:

972613

AN:

1106336

Other (OTH)

AF:

0.848

AC:

51062

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

8935

17870

26806

35741

44676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21154

42308

63462

84616

105770

<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

AF:

0.787

AC:

119683

AN:

152140

Hom.:

48561

Cov.:

AF XY:

0.790

AC XY:

58778

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.564

AC:

23394

AN:

41462

American (AMR)

AF:

0.856

AC:

13099

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.907

AC:

3149

AN:

3470

East Asian (EAS)

AF:

0.855

AC:

4410

AN:

5156

South Asian (SAS)

AF:

0.887

AC:

4279

AN:

4826

European-Finnish (FIN)

AF:

0.867

AC:

9196

AN:

10610

Middle Eastern (MID)

AF:

0.820

AC:

241

AN:

294

European-Non Finnish (NFE)

AF:

0.874

AC:

59396

AN:

67996

Other (OTH)

AF:

0.816

AC:

1724

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1189

2379

3568

4758

5947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.858

Hom.:

52288

Bravo

AF:

0.774

Asia WGS

AF:

0.833

AC:

2894

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.84

(source)

DANN

Benign

0.60

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over