rs34149102

Positions:

• chr10-87863443-C-A
• chr10-87863443-C-G
• chr10-87863443-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

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
• Clinical Significance: Likely benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.0530

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]

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr10-87863443-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 1022 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLLN	NM_001126049.2	c.-956G>T		5_prime_UTR_variant	1/1	ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLLN	ENST00000445946.5	c.-956G>T		5_prime_UTR_variant	1/1	6	NM_001126049.2	ENSP00000392204.2
PTEN	ENST00000693560	c.-507C>A		5_prime_UTR_variant	1/10			ENSP00000509861.1
PTEN	ENST00000688308.1	c.-17+330C>A		intron_variant				ENSP00000508752.1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1023 AN: 152228 Hom.: 6 Cov.: 32

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.: 11 Cov.: 0 AF XY: 0.00838 AC XY: 953 AN XY: 113724

Gnomad4 AFR exome AF: 0.00238

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00588

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00804

GnomAD4 genome AF: 0.00671 AC: 1022 AN: 152342 Hom.: 6 Cov.: 32 AF XY: 0.00661 AC XY: 492 AN XY: 74488

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00685

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 09, 2019	- -

PTEN hamartoma tumor syndrome Benign:2

Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Nov 09, 2016	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) -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KLLN: BS1, BS2; PTEN: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jun 22, 2021

- -

Cowden syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.9
DANN	Benign	0.78

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

Other links and lift over

dbSNP: rs34149102; hg19: chr10-89623200;