NM_001126049.2:c.-923G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

2 publications found

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 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

PTEN links:

MLDHR (HGNC:55481):

MLDHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLLN	NM_001126049.2 link	c.-923G>C		5_prime_UTR_variant	Exon 1 of 1	ENST00000445946.5	NP_001119521.1	B2CW77
PTEN	NM_000314.8 link	c.-1060C>G		upstream_gene_variant		ENST00000371953.8	NP_000305.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLLN	ENST00000445946.5 link	c.-923G>C	5_prime_UTR_variant	Exon 1 of 1	6	NM_001126049.2	ENSP00000392204.2	B2CW77
PTEN	ENST00000371953.8 link	c.-1060C>G	upstream_gene_variant		1	NM_000314.8	ENSP00000361021.3	P60484-1
MLDHR	ENST00000692337.1 link	c.-149C>G	upstream_gene_variant				ENSP00000509326.1

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

African (AFR)

AF:

0.0159

AC:

AN:

6026

American (AMR)

AF:

0.00115

AC:

AN:

6092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7848

East Asian (EAS)

AF:

0.00

AC:

AN:

20220

South Asian (SAS)

AF:

0.00

AC:

AN:

1922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22926

Middle Eastern (MID)

AF:

0.00354

AC:

AN:

1130

European-Non Finnish (NFE)

AF:

0.0000223

AC:

AN:

134230

Other (OTH)

AF:

0.00204

AC:

AN:

13754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00461

AC:

702

AN:

152302

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

319

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0157

AC:

653

AN:

41590

American (AMR)

AF:

0.00235

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67990

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Feb 01, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 04, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25669429, 21633361, 24154570) -

PTEN hamartoma tumor syndrome

Benign:1

Sep 14, 2016

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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

Jan 04, 2024

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

Significance:Likely 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

-0.47

CADD

Benign

4.5

(source)

DANN

Benign

0.75

PhyloP100

-0.28

PromoterAI

0.031

Neutral

(source)

Mutation Taster

=298/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over