dbSNP rs587781357: KLLN:c.-944_-935delCAGGGCAGGG (chr10-87863421-CCCCTGCCCTG-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001126049.2(KLLN):c.-944_-935delCAGGGCAGGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KLLN
NM_001126049.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

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 links:

ENSG00000289051 (HGNC:55481):

ENSG00000289051 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KLLN	NM_001126049.2 link	c.-944_-935delCAGGGCAGGG	5_prime_UTR_variant	Exon 1 of 1	ENST00000445946.5	NP_001119521.1	B2CW77
PTEN	NM_000314.8 link	c.-1048_-1039delCCCTGCCCTG	upstream_gene_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.-528_-519delCCCTGCCCTG	upstream_gene_variant			NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-1753_-1744delCCCTGCCCTG	upstream_gene_variant			NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLLN	ENST00000445946.5 link	c.-944_-935delCAGGGCAGGG	5_prime_UTR_variant	Exon 1 of 1	6	NM_001126049.2	ENSP00000392204.2	B2CW77
PTEN	ENST00000371953.8 link	c.-1048_-1039delCCCTGCCCTG	upstream_gene_variant		1	NM_000314.8	ENSP00000361021.3	P60484-1
ENSG00000289051	ENST00000692337.1 link	c.-137_-128delCCCTGCCCTG	upstream_gene_variant				ENSP00000509326.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

218352

Hom.:

AF XY:

0.00

AC XY:

AN XY:

110980

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 16, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-1039_-1030del10 gross deletion is located in the 5' untranslated region (5'UTR) of the PTEN gene; however, the exact breakpoints of the deletion were not determined. This variant is located in the promoter region of the PTEN gene, but its potential impact on PTEN regulation has not yet been investigated (Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73:404-11). This nucleotide position is conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over