rs190247406

Variant names:

• chr12-6957662-C-A
• rs190247406
• NM_002831.6:c.1083C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-6957662-C-A
• chr12-6957662-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.550
• Publications: 0 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: 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN6	NM_002831.6	c.1083C>A	p.Cys361*	stop_gained	Exon 10 of 16	ENST00000318974.14	NP_002822.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN6	ENST00000318974.14	c.1083C>A	p.Cys361*	stop_gained	Exon 10 of 16	1	NM_002831.6	ENSP00000326010.9
PTPN6	ENST00000456013.5	c.1083C>A	p.Cys361*	stop_gained	Exon 10 of 16	1		ENSP00000391592.1
PTPN6	ENST00000399448.5	c.1089C>A	p.Cys363*	stop_gained	Exon 10 of 16	1		ENSP00000382376.1
PTPN6	ENST00000416215.6	n.1491C>A		non_coding_transcript_exon_variant	Exon 9 of 15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.03e-7 AC: 1 AN: 1244644 Hom.: 0 Cov.: 49 AF XY: 0.00 AC XY: 0 AN XY: 623058

African (AFR) AF: 0.00 AC: 0 AN: 28120

American (AMR) AF: 0.00 AC: 0 AN: 41384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21822

East Asian (EAS) AF: 0.00 AC: 0 AN: 30724

South Asian (SAS) AF: 0.00 AC: 0 AN: 82736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4992

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 943598

Other (OTH) AF: 0.00 AC: 0 AN: 49900

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		0.55
Vest4		0.97
GERP RS		1.4
Mutation Taster		=1/199	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs190247406; hg19: chr12-7066825;