10-87864564-G-C

Variant names:

• chr10-87864564-G-C
• rs768604051
• NM_000314.8:c.79+16G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000314.8(PTEN):​c.79+16G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,862 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.61
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-87864564-G-C is Benign according to our data. Variant chr10-87864564-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 492342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.79+16G>C		intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.598+16G>C		intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.-627+16G>C		intron	N/A	NP_001291647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.79+16G>C		intron	N/A	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.598+16G>C		intron	N/A	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.79+16G>C		intron	N/A	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251456 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459862 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726414

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.000112 AC: 5 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110216

Other (OTH) AF: 0.0000332 AC: 2 AN: 60330

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	1	PTEN hamartoma tumor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Benign	0.77
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs768604051; hg19: chr10-89624321;