12-6960457-T-C

Variant names:

• chr12-6960457-T-C
• rs759052
• NM_002831.6:c.1673+22T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42
• Publications: 14 publications found

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]

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN6	NM_002831.6	c.1673+22T>C		intron_variant	Intron 14 of 15	ENST00000318974.14	NP_002822.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN6	ENST00000318974.14	c.1673+22T>C		intron_variant	Intron 14 of 15	1	NM_002831.6	ENSP00000326010.9

Frequencies

GnomAD3 genomes AF: 0.787 AC: 119636 AN: 152022 Hom.: 48551 Cov.: 33

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

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.: 38 AF XY: 0.870 AC XY: 629833 AN XY: 724046

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

GnomAD4 genome AF: 0.787 AC: 119683 AN: 152140 Hom.: 48561 Cov.: 33 AF XY: 0.790 AC XY: 58778 AN XY: 74370

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

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.84
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)

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: rs759052; hg19: chr12-7069620;