rs34149102

Variant names:

• chr10-87863443-C-A
• rs34149102
• NM_001126049.2:c.-956G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-87863443-C-A
• chr10-87863443-C-G
• chr10-87863443-C-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.-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:10
• Conservation: PhyloP100: 0.0530
• Publications: 5 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=-0.39).
• 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 VariationId is 138836.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAd4 at 1022 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.-956G>T		5_prime_UTR	Exon 1 of 1	NP_001119521.1	B2CW77
	PTEN	NM_000314.8	MANE Select	c.-1027C>A		upstream_gene	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.-507C>A		upstream_gene	N/A	NP_001291646.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLLN	ENST00000445946.5	TSL:6 MANE Select	c.-956G>T		5_prime_UTR	Exon 1 of 1	ENSP00000392204.2	B2CW77
	PTEN	ENST00000693560.1		c.-507C>A		5_prime_UTR	Exon 1 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000688308.1		c.-17+330C>A		intron	N/A	ENSP00000508752.1	P60484-1

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

African (AFR) AF: 0.00238 AC: 15 AN: 6310

American (AMR) AF: 0.00812 AC: 53 AN: 6528

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 94 AN: 8184

East Asian (EAS) AF: 0.00 AC: 0 AN: 21234

South Asian (SAS) AF: 0.00 AC: 0 AN: 2008

European-Finnish (FIN) AF: 0.00588 AC: 125 AN: 21252

Middle Eastern (MID) AF: 0.0119 AC: 14 AN: 1176

European-Non Finnish (NFE) AF: 0.0102 AC: 1444 AN: 142130

Other (OTH) AF: 0.00804 AC: 117 AN: 14546

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

African (AFR) AF: 0.00159 AC: 66 AN: 41594

American (AMR) AF: 0.00856 AC: 131 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.00669 AC: 71 AN: 10616

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0102 AC: 692 AN: 68026

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00685

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	PTEN hamartoma tumor syndrome (2)
-	-	1	Cowden syndrome 1 (1)
-	-	1	Cowden syndrome 4 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.9
DANN	Benign	0.78
PhyloP100		0.053
PromoterAI		-0.046	Neutral
Mutation Taster		=300/0	polymorphism

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: rs34149102; hg19: chr10-89623200;