chr12-6957662-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002831.6(PTPN6):​c.1083C>T​(p.Cys361Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000905 in 1,394,556 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (4 hom.)
• Consequence: PTPN6 NM_002831.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 12-6957662-C-T is Benign according to our data. Variant chr12-6957662-C-T is described in ClinVar as [Benign]. Clinvar id is 777231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.55 with no splicing effect.
• BS2: High AC in GnomAd4 at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN6	NM_002831.6	c.1083C>T	p.Cys361Cys	synonymous_variant	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>T	p.Cys361Cys	synonymous_variant	Exon 10 of 16	1	NM_002831.6	ENSP00000326010.9
PTPN6	ENST00000456013.5	c.1083C>T	p.Cys361Cys	synonymous_variant	Exon 10 of 16	1		ENSP00000391592.1
PTPN6	ENST00000399448.5	c.1089C>T	p.Cys363Cys	synonymous_variant	Exon 10 of 16	1		ENSP00000382376.1
PTPN6	ENST00000416215.6	n.1491C>T		non_coding_transcript_exon_variant	Exon 9 of 15	2

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 459 AN: 149800 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00172

Gnomad ASJ AF: 0.00524

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000134

Gnomad OTH AF: 0.00337

GnomAD2 exomes AF: 0.00138 AC: 344 AN: 248600 AF XY: 0.00115

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00498

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00381

GnomAD4 exome AF: 0.000644 AC: 801 AN: 1244642 Hom.: 4 Cov.: 49 AF XY: 0.000552 AC XY: 344 AN XY: 623056

African (AFR) AF: 0.0126 AC: 354 AN: 28120

American (AMR) AF: 0.00251 AC: 104 AN: 41382

Ashkenazi Jewish (ASJ) AF: 0.00664 AC: 145 AN: 21822

East Asian (EAS) AF: 0.0000325 AC: 1 AN: 30724

South Asian (SAS) AF: 0.0000967 AC: 8 AN: 82736

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

Middle Eastern (MID) AF: 0.000200 AC: 1 AN: 4992

European-Non Finnish (NFE) AF: 0.000119 AC: 112 AN: 943598

Other (OTH) AF: 0.00152 AC: 76 AN: 49900

GnomAD4 genome AF: 0.00308 AC: 461 AN: 149914 Hom.: 4 Cov.: 32 AF XY: 0.00333 AC XY: 244 AN XY: 73278

African (AFR) AF: 0.00971 AC: 400 AN: 41182

American (AMR) AF: 0.00171 AC: 26 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00524 AC: 18 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 4936

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000134 AC: 9 AN: 67338

Other (OTH) AF: 0.00334 AC: 7 AN: 2098

Alfa AF: 0.00203 Hom.: 1

Bravo AF: 0.00380

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.61
PhyloP100		0.55
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;