10-87863494-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001126049.2(KLLN):c.-1007C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 383,564 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

KLLN
NM_001126049.2 5_prime_UTR

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:7

Conservation

PhyloP100: -0.131

Publications

1 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 10-87863494-G-C is Benign according to our data. Variant chr10-87863494-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 127685.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 174 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126049.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KLLN	NM_001126049.2	MANE Select	c.-1007C>G	5_prime_UTR	Exon 1 of 1	NP_001119521.1
PTEN	NM_000314.8	MANE Select	c.-976G>C	upstream_gene	N/A	NP_000305.3
PTEN	NM_001304717.5		c.-456G>C	upstream_gene	N/A	NP_001291646.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KLLN	ENST00000445946.5	TSL:6 MANE Select	c.-1007C>G	5_prime_UTR	Exon 1 of 1	ENSP00000392204.2
PTEN	ENST00000693560.1		c.-456G>C	5_prime_UTR	Exon 1 of 10	ENSP00000509861.1
PTEN	ENST00000688308.1		c.-17+381G>C	intron	N/A	ENSP00000508752.1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.00162

AC:

374

AN:

231296

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

198

AN XY:

117714

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6520

American (AMR)

AF:

0.000439

AC:

AN:

6826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8514

East Asian (EAS)

AF:

0.00

AC:

AN:

21984

South Asian (SAS)

AF:

0.00

AC:

AN:

2120

European-Finnish (FIN)

AF:

0.00556

AC:

116

AN:

20850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1220

European-Non Finnish (NFE)

AF:

0.00164

AC:

243

AN:

148092

Other (OTH)

AF:

0.000791

AC:

AN:

15170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00114

AC:

174

AN:

152268

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00810

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

68002

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000499

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

May 26, 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 c.-975G>C (also known as c.-976G>C) variant involves the alteration of a non-conserved nucleotide in 5'UTR. One in silico tool predicts a benign outcome for this variant. This variant was found in 55/30846 control chromosomes at a frequency of 0.0017831, which is approximately 285 times the estimated maximal expected allele frequency of a pathogenic PTEN variant (0.0000063), suggesting this variant is likely a benign polymorphism. Although multiple clinical diagnostic laboratories classified this variant as uncertain significance, this variant is classified as benign due to its relatively high frequency in controls.

Oct 23, 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)

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTEN: BS1

Apr 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Mar 15, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

May 05, 2014

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Seizure

Uncertain:1

Aug 16, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1

Jul 09, 2018

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTEN hamartoma tumor syndrome

Benign:1

Jun 25, 2019

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.-975G>C (g.89623251G>C) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). BS1: Allele frequency of 0.006 (0.6%, 21/3466 alleles) in the European (Finnish) subpopulation and 0.002 (0.2%, 30/14,976) in the European (Non-Finnish) subpopulation of the gnomAD cohort. (PMID 27535533) BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributors SCV000187238.1, SCV000149489.5)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.3

(source)

DANN

Benign

0.77

PhyloP100

-0.13

PromoterAI

0.071

Neutral

(source)

Mutation Taster

=297/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over