10-87863443-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001126049.2(KLLN):c.-956G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 375,710 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.0067 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0083 ( 11 hom. )

Consequence

KLLN
NM_001126049.2 5_prime_UTR

Scores

Clinical Significance

Likely benign reviewed by expert panel B:10

Conservation

PhyloP100: 0.0530

Publications

5 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 10-87863443-C-A is Benign according to our data. Variant chr10-87863443-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 138836.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 1022 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLLN	NM_001126049.2 link	c.-956G>T		5_prime_UTR_variant	Exon 1 of 1	ENST00000445946.5	NP_001119521.1	B2CW77
PTEN	NM_000314.8 link	c.-1027C>A		upstream_gene_variant		ENST00000371953.8	NP_000305.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLLN	ENST00000445946.5 link	c.-956G>T	5_prime_UTR_variant	Exon 1 of 1	6	NM_001126049.2	ENSP00000392204.2	B2CW77
PTEN	ENST00000371953.8 link	c.-1027C>A	upstream_gene_variant		1	NM_000314.8	ENSP00000361021.3	P60484-1
MLDHR	ENST00000692337.1 link	c.-116C>A	upstream_gene_variant				ENSP00000509326.1

Frequencies

GnomAD3 genomes

AF:

0.00672

AC:

1023

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00669

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0105

GnomAD4 exome

AF:

0.00834

AC:

1862

AN:

223368

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

953

AN XY:

113724

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

6310

American (AMR)

AF:

0.00812

AC:

AN:

6528

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

8184

East Asian (EAS)

AF:

0.00

AC:

AN:

21234

South Asian (SAS)

AF:

0.00

AC:

AN:

2008

European-Finnish (FIN)

AF:

0.00588

AC:

125

AN:

21252

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

1176

European-Non Finnish (NFE)

AF:

0.0102

AC:

1444

AN:

142130

Other (OTH)

AF:

0.00804

AC:

117

AN:

14546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

191

286

382

477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00671

AC:

1022

AN:

152342

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

492

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41594

American (AMR)

AF:

0.00856

AC:

131

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00124

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00669

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0102

AC:

692

AN:

68026

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.00685

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 18, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 09, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PTEN hamartoma tumor syndrome

Benign:2

Nov 09, 2016

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.-1026C>A (NC_000010.10:g.89623200C>A) meets criteria to be classified as likely 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). BS1: Allele frequency of 0.0056 (0.56%, 173/30,898 alleles) in the gnomAD cohort. (PMID 27535533) BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (Internal laboratory contributor(s) SCV000171228.5) BP5: Variant found in multiple cases with alternate molecular basis for disease. (Internal laboratory contributor(s) SCV000171228.5) -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KLLN: BS1, BS2; PTEN: BS1, BS2 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cowden syndrome 1

Benign:1

Apr 28, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jun 22, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Cowden syndrome 4

Benign:1

Oct 14, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

-0.39

CADD

Benign

8.9

(source)

DANN

Benign

0.78

PhyloP100

0.053

PromoterAI

-0.046

Neutral

(source)

Mutation Taster

=300/0

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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10-87863443-C-A

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