17-75559355-C-A

Position:

• chr17-75559355-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001031803.2(LLGL2):​c.475C>A​(p.Pro159Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LLGL2 NM_001031803.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

Genes affected

LLGL2 (HGNC:6629): (LLGL scribble cell polarity complex component 2) The lethal (2) giant larvae protein of Drosophila plays a role in asymmetric cell division, epithelial cell polarity, and cell migration. This human gene encodes a protein similar to lethal (2) giant larvae of Drosophila. In fly, the protein's ability to localize cell fate determinants is regulated by the atypical protein kinase C (aPKC). In human, this protein interacts with aPKC-containing complexes and is cortically localized in mitotic cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

LLGL2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LLGL2	NM_001031803.2	c.475C>A	p.Pro159Thr	missense_variant	6/26	ENST00000392550.8	NP_001026973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LLGL2	ENST00000392550.8	c.475C>A	p.Pro159Thr	missense_variant	6/26	1	NM_001031803.2	ENSP00000376333.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.475C>A (p.P159T) alteration is located in exon 6 (coding exon 5) of the LLGL2 gene. This alteration results from a C to A substitution at nucleotide position 475, causing the proline (P) at amino acid position 159 to be replaced by a threonine (T). 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	Benign	0.20
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.12	.;.;T;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.0	M;M;M;M;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.0	D;D;D;.;.
REVEL	Benign	0.21
Sift	Benign	0.31	T;T;T;.;.
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.081	B;P;B;P;.
Vest4		0.86
MutPred		0.29		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.82
MPC		0.89
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.34
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-73555436;