17-75558551-C-G

Variant names:

• chr17-75558551-C-G
• NM_001031803.2:c.295C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001031803.2(LLGL2):​c.295C>G​(p.Leu99Val) 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: 1.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL2	NM_001031803.2	c.295C>G	p.Leu99Val	missense_variant	Exon 5 of 26	ENST00000392550.8	NP_001026973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LLGL2	ENST00000392550.8	c.295C>G	p.Leu99Val	missense_variant	Exon 5 of 26	1	NM_001031803.2	ENSP00000376333.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.295C>G (p.L99V) alteration is located in exon 5 (coding exon 4) of the LLGL2 gene. This alteration results from a C to G substitution at nucleotide position 295, causing the leucine (L) at amino acid position 99 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.0058	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.22	T;.;.;T;.;T;.;T;T;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.0046
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.5	.;M;M;M;M;.;.;.;.;.
PhyloP100		1.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	.;N;D;N;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.0030	.;D;D;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D
Polyphen		0.54, 0.35, 0.040	.;P;B;B;B;.;.;.;.;.
Vest4		0.49, 0.54, 0.48, 0.53, 0.48
MutPred		0.53		Gain of ubiquitination at K103 (P = 0.1245);Gain of ubiquitination at K103 (P = 0.1245);Gain of ubiquitination at K103 (P = 0.1245);Gain of ubiquitination at K103 (P = 0.1245);Gain of ubiquitination at K103 (P = 0.1245);Gain of ubiquitination at K103 (P = 0.1245);Gain of ubiquitination at K103 (P = 0.1245);Gain of ubiquitination at K103 (P = 0.1245);Gain of ubiquitination at K103 (P = 0.1245);.;
MVP		0.53
MPC		0.36
ClinPred		0.94	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr17-73554632;