rs144528048

Variant names:

• chr17-75543479-G-A
• rs144528048
• NM_001031803.2:c.53G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001031803.2(LLGL2):​c.53G>A​(p.Arg18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000602 in 1,612,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. R18W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: LLGL2 NM_001031803.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015073061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL2	NM_001031803.2	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 26	ENST00000392550.8	NP_001026973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LLGL2	ENST00000392550.8	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 26	1	NM_001031803.2	ENSP00000376333.4

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.0000963 AC: 24 AN: 249328 AF XY: 0.0000593

Gnomad AFR exome AF: 0.000988

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1459714 Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25 AN XY: 726060

African (AFR) AF: 0.000718 AC: 24 AN: 33430

American (AMR) AF: 0.0000450 AC: 2 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39582

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1110804

Other (OTH) AF: 0.0000829 AC: 5 AN: 60286

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74458

African (AFR) AF: 0.000890 AC: 37 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.0000912 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.53G>A (p.R18Q) alteration is located in exon 2 (coding exon 1) of the LLGL2 gene. This alteration results from a G to A substitution at nucleotide position 53, causing the arginine (R) at amino acid position 18 to be replaced by a glutamine (Q). 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	0.066
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0038	T;.;.;T;.;T;.;T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;D;T;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	-1.3	.;N;N;N;N;.;.;.;.;.
PhyloP100		1.0
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.18	.;N;N;N;.;.;.;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.57	.;T;T;T;.;.;.;.;.;.
Sift4G	Benign	0.88	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0080, 0.013, 0.0040	.;B;B;B;B;.;.;.;.;.
Vest4		0.19, 0.19, 0.19
MVP		0.87
MPC		0.26
ClinPred		0.033	T
GERP RS		2.8
PromoterAI		0.034	Neutral
Varity_R		0.51
gMVP		0.14
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs144528048; hg19: chr17-73539560; COSMIC: COSV51386569; COSMIC: COSV51386569;