rs766498095

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001031803.2(LLGL2):​c.155G>A​(p.Arg52His) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,610,118 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R52C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

LLGL2
NM_001031803.2 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

Publications

2 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34963325).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LLGL2NM_001031803.2 linkc.155G>A p.Arg52His missense_variant Exon 3 of 26 ENST00000392550.8 NP_001026973.1 Q6P1M3-1A0PJJ0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LLGL2ENST00000392550.8 linkc.155G>A p.Arg52His missense_variant Exon 3 of 26 1 NM_001031803.2 ENSP00000376333.4 Q6P1M3-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000805
AC:
2
AN:
248340
AF XY:
0.00000743
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000892
AC:
13
AN:
1457782
Hom.:
0
Cov.:
32
AF XY:
0.00000689
AC XY:
5
AN XY:
725484
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39690
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86258
European-Finnish (FIN)
AF:
0.0000202
AC:
1
AN:
49516
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000540
AC:
6
AN:
1111854
Other (OTH)
AF:
0.00
AC:
0
AN:
60366
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152336
Hom.:
0
Cov.:
32
AF XY:
0.0000268
AC XY:
2
AN XY:
74494
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
AN:
41574
American (AMR)
AF:
0.00
AC:
0
AN:
15306
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5184
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 15, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.155G>A (p.R52H) alteration is located in exon 3 (coding exon 2) of the LLGL2 gene. This alteration results from a G to A substitution at nucleotide position 155, causing the arginine (R) at amino acid position 52 to be replaced by a histidine (H). 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
0.16
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.075
T;.;.;T;.;T;.;T;T;.
Eigen
Benign
0.019
Eigen_PC
Benign
0.066
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Pathogenic
0.99
D;D;.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.35
T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Benign
1.7
.;L;L;L;L;.;.;.;.;.
PhyloP100
3.6
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-2.2
.;N;D;N;.;.;.;.;.;.
REVEL
Uncertain
0.60
Sift
Benign
0.059
.;T;D;T;.;.;.;.;.;.
Sift4G
Uncertain
0.015
D;T;T;T;T;D;T;D;D;D
Polyphen
0.21, 0.60, 0.16
.;B;P;B;P;.;.;.;.;.
Vest4
0.56, 0.60, 0.57, 0.56
MutPred
0.53
Loss of methylation at R52 (P = 0.0168);Loss of methylation at R52 (P = 0.0168);Loss of methylation at R52 (P = 0.0168);Loss of methylation at R52 (P = 0.0168);Loss of methylation at R52 (P = 0.0168);Loss of methylation at R52 (P = 0.0168);Loss of methylation at R52 (P = 0.0168);Loss of methylation at R52 (P = 0.0168);Loss of methylation at R52 (P = 0.0168);.;
MVP
0.85
MPC
0.37
ClinPred
0.33
T
GERP RS
3.7
Varity_R
0.29
gMVP
0.70
Mutation Taster
=79/21
polymorphism

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

Other links and lift over

dbSNP: rs766498095; hg19: chr17-73552206; COSMIC: COSV51346584; COSMIC: COSV51346584; API