10-87863410-C-G

Position:

chr10-87863410-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: PTEN c.-1059C>G (NC_000010.10:g.89623167C>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.0138 (1.38%, 120/8698 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) LINK:https://erepo.genome.network/evrepo/ui/classification/CA300594/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.0046 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 3 hom. )

Consequence

KLLN
NM_001126049.2 5_prime_UTR

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: -0.280

Variant links:

Genes affected

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

KLLN links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLLN	NM_001126049.2 linkuse as main transcript	c.-923G>C		5_prime_UTR_variant	1/1	ENST00000445946.5

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Appris	UniProt
KLLN	ENST00000445946.5 linkuse as main transcript	c.-923G>C	5_prime_UTR_variant	1/1	NM_001126049.2	P1
PTEN	ENST00000688308.1 linkuse as main transcript	c.-17+297C>G	intron_variant			P1	P60484-1
PTEN	ENST00000693560.1 linkuse as main transcript		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

702

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.000644

AC:

138

AN:

214148

Hom.:

Cov.:

AF XY:

0.000487

AC XY:

AN XY:

108840

show subpopulations

Gnomad4 AFR exome

AF:

0.0159

Gnomad4 AMR exome

AF:

0.00115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000223

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00461

AC:

702

AN:

152302

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

319

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0157

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000836

Hom.:

Bravo

AF:

0.00517

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2017	Variant summary: The PTEN variant c.-1059C>G (also known as c.-1060C>G) involves the alteration of a non-conserved nucleotide located in the 5' UTR. The variant of interest was observed in 1000 Gs with an allele frequency of 19/5008 (1/270), predominantly in the African cohort, 18/1322 (1/73), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PTEN variant of 1/158730 for Cowden syndrome and 1/64102 for HBOC. Therefore, suggesting this variant is likely a benign polymorphism found predominantly in population(s) of African origin. Furthermore, another large, broad control population, gnomAD, which is currently only in early beta mode, cites the variant with an allele frequency of 119/8482 (2 homozygotes) in Africans, further supporting the variant being a benign polymorphism. However, of note, the variant has been depicted in ClinVar as c.-1059C>G (the variant's legacy name), with a classification of "likely benign." The variant has been reported in publications and has indicated that it could affect expression. However, due to the high frequency in controls and the supporting classification by a clinical diagnostic laboratory as "likely benign," the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2017	This variant is associated with the following publications: (PMID: 25669429, 21633361, 24154570) -

PTEN hamartoma tumor syndrome

Benign:1

Benign, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Sep 14, 2016

PTEN c.-1059C>G (NC_000010.10:g.89623167C>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BA1: Allele frequency of 0.0138 (1.38%, 120/8698 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.5

DANN

Benign

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over