rs1671036

Positions:

• chr17-75556104-G-A
• chr17-75556104-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001031803.2(LLGL2):​c.134G>A​(p.Arg45His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,609,404 control chromosomes in the GnomAD database, including 232,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (16485 hom., cov: 32)
  • Exomes 𝑓: 0.54 (215725 hom.)
• Consequence: LLGL2 NM_001031803.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.42

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6456906E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LLGL2	NM_001031803.2	c.134G>A	p.Arg45His	missense_variant	3/26	ENST00000392550.8	NP_001026973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LLGL2	ENST00000392550.8	c.134G>A	p.Arg45His	missense_variant	3/26	1	NM_001031803.2	ENSP00000376333	P4

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65884 AN: 151954 Hom.: 16484 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.474

GnomAD3 exomes AF: 0.501 AC: 124162 AN: 248074 Hom.: 33164 AF XY: 0.522 AC XY: 70220 AN XY: 134552

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.564

Gnomad EAS exome AF: 0.449

Gnomad SAS exome AF: 0.628

Gnomad FIN exome AF: 0.539

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.522

GnomAD4 exome AF: 0.538 AC: 784332 AN: 1457332 Hom.: 215725 Cov.: 47 AF XY: 0.544 AC XY: 394401 AN XY: 725286

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.568

Gnomad4 EAS exome AF: 0.460

Gnomad4 SAS exome AF: 0.623

Gnomad4 FIN exome AF: 0.541

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 0.526

GnomAD4 genome AF: 0.433 AC: 65903 AN: 152072 Hom.: 16485 Cov.: 32 AF XY: 0.435 AC XY: 32332 AN XY: 74332

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.425

Gnomad4 ASJ AF: 0.562

Gnomad4 EAS AF: 0.469

Gnomad4 SAS AF: 0.609

Gnomad4 FIN AF: 0.532

Gnomad4 NFE AF: 0.556

Gnomad4 OTH AF: 0.477

Alfa AF: 0.530 Hom.: 28057

Bravo AF: 0.407

TwinsUK AF: 0.554 AC: 2053

ALSPAC AF: 0.548 AC: 2113

ESP6500AA AF: 0.176 AC: 774

ESP6500EA AF: 0.550 AC: 4733

ExAC AF: 0.501 AC: 60778

Asia WGS AF: 0.535 AC: 1863 AN: 3478

EpiCase AF: 0.563

EpiControl AF: 0.567

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.10	T;.;.;T;.;T;.;T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.84	T;D;.;D;D;D;D;D;T;T
MetaRNN	Benign	0.000026	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.49	.;N;N;N;N;.;.;.;.;.
MutationTaster	Benign	0.87	P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.7	.;D;D;D;.;.;.;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.069	.;T;T;T;.;.;.;.;.;.
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T;T
Polyphen		0.054, 0.0060, 0.0030	.;B;B;B;B;.;.;.;.;.
Vest4		0.071, 0.12, 0.072, 0.12, 0.070
MPC		0.28
ClinPred		0.0067	T
GERP RS		3.6
Varity_R		0.31
gMVP		0.37

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: rs1671036; hg19: chr17-73552185; COSMIC: COSV51344491; COSMIC: COSV51344491;