rs2736627

Variant names:

• chr10-87961337-C-T
• rs2736627
• NM_000314.8:c.1026+219C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.893
• Publications: 11 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• 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 -20 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 VariationId is 1245322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1026+219C>T		intron_variant	Intron 8 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1545+219C>T		intron_variant	Intron 9 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.435+219C>T		intron_variant	Intron 8 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1026+219C>T		intron_variant	Intron 8 of 8	1	NM_000314.8	ENSP00000361021.3

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

African (AFR) AF: 0.978 AC: 10607 AN: 10842

American (AMR) AF: 0.914 AC: 14265 AN: 15606

Ashkenazi Jewish (ASJ) AF: 0.839 AC: 9415 AN: 11224

East Asian (EAS) AF: 1.00 AC: 24713 AN: 24716

South Asian (SAS) AF: 0.968 AC: 38246 AN: 39502

European-Finnish (FIN) AF: 0.923 AC: 18779 AN: 20340

Middle Eastern (MID) AF: 0.869 AC: 1388 AN: 1598

European-Non Finnish (NFE) AF: 0.883 AC: 198227 AN: 224386

Other (OTH) AF: 0.901 AC: 19171 AN: 21282

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

African (AFR) AF: 0.982 AC: 40792 AN: 41546

American (AMR) AF: 0.907 AC: 13860 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2906 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5182

South Asian (SAS) AF: 0.972 AC: 4689 AN: 4826

European-Finnish (FIN) AF: 0.930 AC: 9851 AN: 10594

Middle Eastern (MID) AF: 0.887 AC: 259 AN: 292

European-Non Finnish (NFE) AF: 0.881 AC: 59936 AN: 68000

Other (OTH) AF: 0.903 AC: 1908 AN: 2112

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.0
DANN	Benign	0.68
PhyloP100		0.89
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: rs2736627; hg19: chr10-89721094;