rs2736627

Positions:

• chr10-87961337-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000314.8(PTEN):​c.1026+219C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 521,718 control chromosomes in the GnomAD database, including 216,918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.92 (64833 hom., cov: 31)
  • Exomes 𝑓: 0.91 (152085 hom.)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.893

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-87961337-C-T is Benign according to our data. Variant chr10-87961337-C-T is described in ClinVar as [Benign]. Clinvar id is 1245322.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961337-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.1026+219C>T		intron_variant		ENST00000371953.8
PTEN	NM_001304717.5	c.1545+219C>T		intron_variant
PTEN	NM_001304718.2	c.436+219C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.1026+219C>T		intron_variant		1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.921 AC: 140132 AN: 152104 Hom.: 64767 Cov.: 31

Gnomad AFR AF: 0.982

Gnomad AMI AF: 0.959

Gnomad AMR AF: 0.906

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.972

Gnomad FIN AF: 0.930

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.902

GnomAD4 exome AF: 0.906 AC: 334811 AN: 369496 Hom.: 152085 Cov.: 4 AF XY: 0.908 AC XY: 177769 AN XY: 195732

Gnomad4 AFR exome AF: 0.978

Gnomad4 AMR exome AF: 0.914

Gnomad4 ASJ exome AF: 0.839

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.968

Gnomad4 FIN exome AF: 0.923

Gnomad4 NFE exome AF: 0.883

Gnomad4 OTH exome AF: 0.901

GnomAD4 genome AF: 0.921 AC: 140256 AN: 152222 Hom.: 64833 Cov.: 31 AF XY: 0.924 AC XY: 68755 AN XY: 74416

Gnomad4 AFR AF: 0.982

Gnomad4 AMR AF: 0.907

Gnomad4 ASJ AF: 0.837

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.972

Gnomad4 FIN AF: 0.930

Gnomad4 NFE AF: 0.881

Gnomad4 OTH AF: 0.903

Alfa AF: 0.901 Hom.: 7689

Bravo AF: 0.922

Asia WGS AF: 0.983 AC: 3418 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.0
DANN	Benign	0.68

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: rs2736627; hg19: chr10-89721094;