rs786204885

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001126049.2(KLLN):c.-794_-783delTGCGGCTTTTGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 233,666 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

KLLN
NM_001126049.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel U:2B:6

Conservation

PhyloP100: 2.18

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

Variant 10-87863269-TGCAAAAGCCGCA-T is Benign according to our data. Variant chr10-87863269-TGCAAAAGCCGCA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 189433.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 36 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLLN	NM_001126049.2 link	c.-794_-783delTGCGGCTTTTGC		5_prime_UTR_variant	Exon 1 of 1	ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
KLLN	ENST00000445946.5 link	c.-794_-783delTGCGGCTTTTGC	5_prime_UTR_variant	Exon 1 of 1	6	NM_001126049.2	ENSP00000392204.2
PTEN	ENST00000688308.1 link	c.-17+161_-17+172delAAGCCGCAGCAA	intron_variant	Intron 1 of 9			ENSP00000508752.1
PTEN	ENST00000693560.1 link	c.-680_-669delGCAAAAGCCGCA	upstream_gene_variant				ENSP00000509861.1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.000221

AC:

AN:

81476

Hom.:

AF XY:

0.000203

AC XY:

AN XY:

39340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

2576

American (AMR)

AF:

0.000580

AC:

AN:

1724

Ashkenazi Jewish (ASJ)

AF:

0.000298

AC:

AN:

3358

East Asian (EAS)

AF:

0.00

AC:

AN:

8050

South Asian (SAS)

AF:

0.00

AC:

AN:

662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

394

European-Non Finnish (NFE)

AF:

0.000379

AC:

AN:

42268

Other (OTH)

AF:

0.00

AC:

AN:

5132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

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:

0.000237

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.000262

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68024

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000285

Hom.:

Bravo

AF:

0.000332

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Mar 26, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21194675, 21956414, 25669429, 28821472, 28157521, 21532617)

May 16, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KLLN: BS1, BS2; PTEN: BS1, BS2

Oct 11, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTEN hamartoma tumor syndrome

Uncertain:1Benign:1

Jul 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant occurs in a non-coding region of the PTEN gene. It does not change the encoded amino acid sequence of the PTEN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with clinical features of Cowden syndrome (PMID: 21194675, 21532617). This variant is also known as c.-1195del12 in the literature. ClinVar contains an entry for this variant (Variation ID: 189433). This variant has been reported to have conflicting or insufficient data to determine the effect on PTEN protein function (PMID: 21532617). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Mar 05, 2019

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.-1195del12 (NC_000010.10:g.89623031_89623042delAAGCCGCAGCAA) 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). BS4_P: Lack of segregation in affected members of one family. (Internal laboratory contributor SCV SCV000222146.7) BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributors SCV000222146.7, SCV000183826.5)

Hereditary cancer-predisposing syndrome

Benign:2

Sep 12, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 24, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=115/185

disease causing

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over