rs587780001

Variant names:

• chr10-87863494-G-A
• rs587780001
• NM_001126049.2:c.-1007C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-87863494-G-A
• chr10-87863494-G-C
• chr10-87863494-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001126049.2(KLLN):​c.-1007C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 383,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: KLLN NM_001126049.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: -0.131
• Publications: 1 publications found

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]

PTEN Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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

MLDHR (HGNC:55481):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-87863494-G-A is Benign according to our data. Variant chr10-87863494-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 127684.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAd4 at 139 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126049.2. 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
	KLLN	NM_001126049.2	MANE Select	c.-1007C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	NP_001119521.1	B2CW77
	KLLN	NM_001126049.2	MANE Select	c.-1007C>T		5_prime_UTR	Exon 1 of 1	NP_001119521.1	B2CW77
	PTEN	NM_000314.8	MANE Select	c.-976G>A		upstream_gene	N/A	NP_000305.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLLN	ENST00000445946.5	TSL:6 MANE Select	c.-1007C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	ENSP00000392204.2	B2CW77
	KLLN	ENST00000445946.5	TSL:6 MANE Select	c.-1007C>T		5_prime_UTR	Exon 1 of 1	ENSP00000392204.2	B2CW77
	PTEN	ENST00000693560.1		c.-456G>A		5_prime_UTR	Exon 1 of 10	ENSP00000509861.1	A0A8I5KSF9

Frequencies

GnomAD3 genomes AF: 0.000914 AC: 139 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000493 AC: 114 AN: 231298 Hom.: 0 Cov.: 0 AF XY: 0.000569 AC XY: 67 AN XY: 117714

African (AFR) AF: 0.00153 AC: 10 AN: 6520

American (AMR) AF: 0.000879 AC: 6 AN: 6826

Ashkenazi Jewish (ASJ) AF: 0.00270 AC: 23 AN: 8514

East Asian (EAS) AF: 0.00 AC: 0 AN: 21984

South Asian (SAS) AF: 0.00 AC: 0 AN: 2120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20850

Middle Eastern (MID) AF: 0.000820 AC: 1 AN: 1220

European-Non Finnish (NFE) AF: 0.000351 AC: 52 AN: 148094

Other (OTH) AF: 0.00145 AC: 22 AN: 15170

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74452

African (AFR) AF: 0.00173 AC: 72 AN: 41568

American (AMR) AF: 0.00150 AC: 23 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68002

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)
-	-	1	PTEN hamartoma tumor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.91
PhyloP100		-0.13
PromoterAI		-0.013	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: rs587780001; hg19: chr10-89623251;