17-75556091-A-G

Variant names:

• chr17-75556091-A-G
• rs868300040
• NM_001031803.2:c.121A>G

Variant summary

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

The NM_001031803.2(LLGL2):​c.121A>G​(p.Ser41Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,098 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: LLGL2 NM_001031803.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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=0.33446983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL2	NM_001031803.2	c.121A>G	p.Ser41Gly	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.121A>G	p.Ser41Gly	missense_variant	Exon 3 of 26	1	NM_001031803.2	ENSP00000376333.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248034 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457912 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6 AN XY: 725560

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121A>G (p.S41G) alteration is located in exon 3 (coding exon 2) of the LLGL2 gene. This alteration results from a A to G substitution at nucleotide position 121, causing the serine (S) at amino acid position 41 to be replaced by a glycine (G). 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	0.22
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Benign	0.75
DEOGEN2	Benign	0.088	T;.;.;T;.;T;.;T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.2	.;M;M;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	.;N;N;N;.;.;.;.;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.0070	.;D;D;D;.;.;.;.;.;.
Sift4G	Benign	0.14	T;D;D;D;D;T;D;T;T;T
Polyphen		0.86, 0.99, 0.65	.;P;D;P;D;.;.;.;.;.
Vest4		0.73, 0.73, 0.73, 0.73
MutPred		0.64		Loss of disorder (P = 0.1143);Loss of disorder (P = 0.1143);Loss of disorder (P = 0.1143);Loss of disorder (P = 0.1143);Loss of disorder (P = 0.1143);Loss of disorder (P = 0.1143);Loss of disorder (P = 0.1143);Loss of disorder (P = 0.1143);Loss of disorder (P = 0.1143);.;
MVP		0.75
MPC		0.66
ClinPred		0.38	T
GERP RS		4.7
Varity_R		0.56
gMVP		0.73

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: rs868300040; hg19: chr17-73552172;