NM_001031803.2:c.133C>G

Variant names:

• chr17-75556103-C-G
• rs748801213
• NM_001031803.2:c.133C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001031803.2(LLGL2):​c.133C>G​(p.Arg45Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LLGL2 NM_001031803.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3814948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL2	NM_001031803.2	c.133C>G	p.Arg45Gly	missense_variant	Exon 3 of 26	ENST00000392550.8	NP_001026973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LLGL2	ENST00000392550.8	c.133C>G	p.Arg45Gly	missense_variant	Exon 3 of 26	1	NM_001031803.2	ENSP00000376333.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248380 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458186 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.79
DEOGEN2	Benign	0.11	T;.;.;T;.;T;.;T;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;D;.;D;D;D;D;D;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.6	.;L;L;L;L;.;.;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.2	.;D;D;D;.;.;.;.;.;.
REVEL	Benign	0.12
Sift	Uncertain	0.0040	.;D;D;D;.;.;.;.;.;.
Sift4G	Uncertain	0.034	D;T;T;T;T;D;T;D;D;D
Polyphen		0.44, 0.27, 0.042	.;B;B;B;B;.;.;.;.;.
Vest4		0.53, 0.55, 0.53, 0.54, 0.52
MutPred		0.41		Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);.;
MVP		0.73
MPC		0.31
ClinPred		0.89	D
GERP RS		4.5
Varity_R		0.64
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs748801213; hg19: chr17-73552184;