10-101003518-G-C

Variant names:

• chr10-101003518-G-C
• rs151215972
• NM_001318100.2:c.420G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001318100.2(LZTS2):​c.420G>C​(p.Lys140Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000679 in 1,516,608 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: LZTS2 NM_001318100.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

Genes affected

LZTS2 (HGNC:29381): (leucine zipper tumor suppressor 2) The protein encoded by this gene belongs to the leucine zipper tumor suppressor family of proteins, which function in transcription regulation and cell cycle control. This family member can repress beta-catenin-mediated transcriptional activation and is a negative regulator of the Wnt signaling pathway. It negatively regulates microtubule severing at centrosomes, and is necessary for central spindle formation and cytokinesis completion. It is implicated in cancer, where it may inhibit cell proliferation and decrease susceptibility to tumor development. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17672211).
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LZTS2	NM_001318100.2	c.420G>C	p.Lys140Asn	missense_variant	Exon 3 of 5	ENST00000454422.2	NP_001305029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LZTS2	ENST00000454422.2	c.420G>C	p.Lys140Asn	missense_variant	Exon 3 of 5	2	NM_001318100.2	ENSP00000416972.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000140 AC: 25 AN: 178508 Hom.: 0 AF XY: 0.000128 AC XY: 12 AN XY: 93706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000588

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000696 AC: 95 AN: 1364410 Hom.: 0 Cov.: 31 AF XY: 0.0000614 AC XY: 41 AN XY: 667552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000338

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000101

Gnomad4 NFE exome AF: 0.0000770

Gnomad4 OTH exome AF: 0.000125

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000153 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.420G>C (p.K140N) alteration is located in exon 3 (coding exon 2) of the LZTS2 gene. This alteration results from a G to C substitution at nucleotide position 420, causing the lysine (K) at amino acid position 140 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T;T;.
Eigen	Benign	0.082
Eigen_PC	Benign	-0.0054
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;.;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	.;M;.;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.025	D;D;D;D;D
Sift4G	Uncertain	0.017	D;T;D;T;D
Polyphen		1.0	.;D;.;D;.
Vest4		0.62, 0.62
MutPred		0.31		Loss of methylation at K140 (P = 0.0048);Loss of methylation at K140 (P = 0.0048);Loss of methylation at K140 (P = 0.0048);Loss of methylation at K140 (P = 0.0048);Loss of methylation at K140 (P = 0.0048);
MVP		0.38
MPC		0.94
ClinPred		0.35	T
GERP RS		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs151215972; hg19: chr10-102763275;