10-87863421-CCCCTGCCCTG-CCCCTGCCCTGCCCTG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001126049.2(KLLN):​c.-939_-935dupCAGGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 370,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

KLLN
NM_001126049.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.159
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KLLNNM_001126049.2 linkc.-939_-935dupCAGGG 5_prime_UTR_variant 1/1 ENST00000445946.5 NP_001119521.1 B2CW77

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KLLNENST00000445946.5 linkc.-939_-935dupCAGGG 5_prime_UTR_variant 1/16 NM_001126049.2 ENSP00000392204.2 B2CW77
PTENENST00000693560 linkc.-514_-510dupGCCCT 5_prime_UTR_variant 1/10 ENSP00000509861.1 A0A8I5KSF9
PTENENST00000688308.1 linkc.-17+323_-17+327dupGCCCT intron_variant ENSP00000508752.1 P60484-1
PTENENST00000693560.1 linkc.-529_-528insCCCTG upstream_gene_variant ENSP00000509861.1 A0A8I5KSF9

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000687
AC:
15
AN:
218352
Hom.:
0
Cov.:
0
AF XY:
0.0000721
AC XY:
8
AN XY:
110980
show subpopulations
Gnomad4 AFR exome
AF:
0.00114
Gnomad4 AMR exome
AF:
0.000160
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000509
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000363
Gnomad4 OTH exome
AF:
0.0000711
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoAug 22, 2024The PTEN c.-1034_-1030dup variant has been reported in the published literature in a study of patients with PTEN variants who had available brain magnetic resonance imaging (MRI), the patient who was positive for the variant showed no discrete malformation of cortical development (PMID: 32959437 (2020)). The frequency of this variant in the general population, 0.00058 (5/8680 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 11, 2019Has not been previously published as pathogenic or benign to our knowledge; Variants within the PTEN promoter have been observed in individuals with features of Cowden syndrome (Zhou 2003); Also known as c.-1033_-1029dupGCCCT; This variant is associated with the following publications: (PMID: 12844284, 22679820) -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 28, 2023Variant summary: PTEN c.-1034_-1030dupGCCCT is located in the untranslated mRNA region upstream of the initiation codon, and involves the insertion of five nucleotides in the PTEN promoter region; variants in this region might alter transcription, which could result in impaired mRNA expression. PTEN is unique in that its promoter and its 5 UTR overlap, so variants in this region might also affect mRNA splicing and protein translation. The variant allele was found at a frequency of 0.00012 in 370652 control chromosomes (gnomAD v4.0.0). The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06),, suggesting that the variant may be benign. To our knowledge, no occurrence of c.-1034_-1030dupGCCCT in individuals affected with PTEN-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. The following publication was ascertained in the context of this evaluation (PMID: 32959437). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 16, 2013- -

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.

Other links and lift over

dbSNP: rs587781357; hg19: chr10-89623178; API