10-87863549-G-C

Variant names:

• chr10-87863549-G-C
• rs786204937
• ENST00000693560.1:c.-401G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000693560.1(PTEN):​c.-401G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000854 in 234,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: PTEN ENST00000693560.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.568
• Publications: 0 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 4

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

MLDHR (HGNC:55481):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000693560.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.-921G>C		upstream_gene	N/A	NP_000305.3
	KLLN	NM_001126049.2	MANE Select	c.-1062C>G		upstream_gene	N/A	NP_001119521.1	B2CW77
	PTEN	NM_001304717.5		c.-401G>C		upstream_gene	N/A	NP_001291646.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000693560.1		c.-401G>C		5_prime_UTR	Exon 1 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000688308.1		c.-17+436G>C		intron	N/A	ENSP00000508752.1	P60484-1
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.-921G>C		upstream_gene	N/A	ENSP00000361021.3	P60484-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000854 AC: 2 AN: 234200 Hom.: 0 Cov.: 0 AF XY: 0.00000840 AC XY: 1 AN XY: 119058

African (AFR) AF: 0.00 AC: 0 AN: 6598

American (AMR) AF: 0.00 AC: 0 AN: 6950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8604

East Asian (EAS) AF: 0.00 AC: 0 AN: 22224

South Asian (SAS) AF: 0.00 AC: 0 AN: 2690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1242

European-Non Finnish (NFE) AF: 0.00000667 AC: 1 AN: 149872

Other (OTH) AF: 0.0000650 AC: 1 AN: 15390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.86
PhyloP100		0.57
PromoterAI		0.023	Neutral

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

Other links and lift over

dbSNP: rs786204937; hg19: chr10-89623306;