rs2301756

Variant names:

• chr12-112452972-A-G
• rs2301756
• NM_002834.5:c.333-223A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-112452972-A-G
• chr12-112452972-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002834.5(PTPN11):​c.333-223A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 151,938 control chromosomes in the GnomAD database, including 5,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.21 (5587 hom., cov: 32)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.536
• Publications: 31 publications found

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) 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. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

PTPN11 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000305447 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-112452972-A-G is Benign according to our data. Variant chr12-112452972-A-G is described in ClinVar as Benign. ClinVar VariationId is 561607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.333-223A>G		intron_variant	Intron 3 of 15	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.333-223A>G		intron_variant	Intron 3 of 15	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.333-223A>G		intron_variant	Intron 3 of 14	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32330 AN: 151820 Hom.: 5584 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.0963

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.213 AC: 32377 AN: 151938 Hom.: 5587 Cov.: 32 AF XY: 0.219 AC XY: 16233 AN XY: 74286

African (AFR) AF: 0.357 AC: 14769 AN: 41408

American (AMR) AF: 0.238 AC: 3636 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3468

East Asian (EAS) AF: 0.856 AC: 4423 AN: 5170

South Asian (SAS) AF: 0.245 AC: 1181 AN: 4818

European-Finnish (FIN) AF: 0.115 AC: 1210 AN: 10540

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.0963 AC: 6545 AN: 67968

Other (OTH) AF: 0.194 AC: 410 AN: 2112

Alfa AF: 0.159 Hom.: 2162

Bravo AF: 0.234

Asia WGS AF: 0.481 AC: 1670 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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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	-0.92
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		-0.54
PromoterAI		-0.0052	Neutral
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: rs2301756; hg19: chr12-112890776;