rs376702513

Positions:

• chr10-87960876-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_000314.8(PTEN):​c.802-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,299,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0610

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

PTEN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Variant has high frequency in the EAS(2.6633E-4) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-87960876-C-T is Benign according to our data. Variant chr10-87960876-C-T is described in ClinVar as [Benign]. Clinvar id is 92830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87960876-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.802-18C>T		intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1321-18C>T		intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.211-18C>T		intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.802-18C>T		intron_variant		1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 52 AN: 125024 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000231

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000639

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000357

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00185 AC: 2409 AN: 1299150 Hom.: 0 Cov.: 30 AF XY: 0.00197 AC XY: 1276 AN XY: 646836

Gnomad4 AFR exome AF: 0.00353

Gnomad4 AMR exome AF: 0.00377

Gnomad4 ASJ exome AF: 0.00324

Gnomad4 EAS exome AF: 0.00986

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.000987

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000424 AC: 53 AN: 125022 Hom.: 0 Cov.: 28 AF XY: 0.000563 AC XY: 34 AN XY: 60384

Gnomad4 AFR AF: 0.000441

Gnomad4 AMR AF: 0.000231

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000641

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00173

Gnomad4 NFE AF: 0.000357

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00143 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 23, 2021

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Jan 21, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.21

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

LitVar

Other links and lift over

dbSNP: rs376702513; hg19: chr10-89720633;