chr17-75558566-G-A

Variant names:

• chr17-75558566-G-A
• rs774877468
• NM_001031803.2:c.310G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001031803.2(LLGL2):​c.310G>A​(p.Val104Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,459,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. V104F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: LLGL2 NM_001031803.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10572803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL2	NM_001031803.2	c.310G>A	p.Val104Ile	missense_variant	Exon 5 of 26	ENST00000392550.8	NP_001026973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LLGL2	ENST00000392550.8	c.310G>A	p.Val104Ile	missense_variant	Exon 5 of 26	1	NM_001031803.2	ENSP00000376333.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 246372 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000103 AC: 15 AN: 1459510 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725800

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000584 AC: 5 AN: 85640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111156

Other (OTH) AF: 0.0000166 AC: 1 AN: 60264

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.020	T;.;.;T;.;.;T;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.62	T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.69	.;N;N;N;N;.;.;.;.
PhyloP100		3.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.35	.;N;N;N;.;.;.;.;.
REVEL	Benign	0.038
Sift	Benign	0.20	.;T;T;T;.;.;.;.;.
Sift4G	Benign	0.55	T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.065, 0.0	.;B;B;B;B;.;.;.;.
Vest4		0.078, 0.081, 0.083
MutPred		0.27		Gain of catalytic residue at V104 (P = 0.0368);Gain of catalytic residue at V104 (P = 0.0368);Gain of catalytic residue at V104 (P = 0.0368);Gain of catalytic residue at V104 (P = 0.0368);Gain of catalytic residue at V104 (P = 0.0368);Gain of catalytic residue at V104 (P = 0.0368);Gain of catalytic residue at V104 (P = 0.0368);Gain of catalytic residue at V104 (P = 0.0368);.;
MVP		0.50
MPC		0.18
ClinPred		0.052	T
GERP RS		0.89
Varity_R		0.060
gMVP		0.22
Mutation Taster		=90/10	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: rs774877468; hg19: chr17-73554647;