17-75543431-G-C

Position:

• chr17-75543431-G-C

Variant summary

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

The NM_001031803.2(LLGL2):​c.5G>C​(p.Arg2Thr) variant causes a missense change involving the alteration of a non-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: 2.91

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]

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.5G>C	p.Arg2Thr	missense_variant	2/26	ENST00000392550.8	NP_001026973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LLGL2	ENST00000392550.8	c.5G>C	p.Arg2Thr	missense_variant	2/26	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

May 24, 2023

The c.5G>C (p.R2T) alteration is located in exon 2 (coding exon 1) of the LLGL2 gene. This alteration results from a G to C substitution at nucleotide position 5, causing the arginine (R) at amino acid position 2 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.025	T;.;.;T;.;T;.;T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	0.76	.;N;N;N;N;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	.;N;N;N;.;.;.;.;.;.
REVEL	Uncertain	0.56
Sift	Benign	0.15	.;T;T;T;.;.;.;.;.;.
Sift4G	Uncertain	0.013	D;T;T;T;T;D;T;D;D;D
Polyphen		0.48, 0.90, 0.65	.;P;P;P;P;.;.;.;.;.
Vest4		0.57, 0.57, 0.57, 0.56
MutPred		0.35		Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);Loss of methylation at R2 (P = 0.0142);
MVP		0.94
MPC		0.58
ClinPred		0.82	D
GERP RS		4.8
Varity_R		0.21
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-73539512;