17-75569090-T-C

Variant names:

• chr17-75569090-T-C
• rs1671021
• NM_001031803.2:c.1435T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001031803.2(LLGL2):​c.1435T>C​(p.Phe479Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,612,362 control chromosomes in the GnomAD database, including 128,083 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. F479V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.49 (21364 hom., cov: 33)
  • Exomes 𝑓: 0.37 (106719 hom.)
• Consequence: LLGL2 NM_001031803.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 42 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.281977E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031803.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LLGL2	NM_001031803.2	MANE Select	c.1435T>C	p.Phe479Leu	missense	Exon 13 of 26	NP_001026973.1
	LLGL2	NM_004524.3		c.1435T>C	p.Phe479Leu	missense	Exon 13 of 25	NP_004515.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LLGL2	ENST00000392550.8	TSL:1 MANE Select	c.1435T>C	p.Phe479Leu	missense	Exon 13 of 26	ENSP00000376333.4
	LLGL2	ENST00000577200.5	TSL:1	c.1435T>C	p.Phe479Leu	missense	Exon 13 of 26	ENSP00000464397.1
	LLGL2	ENST00000167462.9	TSL:1	c.1435T>C	p.Phe479Leu	missense	Exon 13 of 25	ENSP00000167462.5

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73674 AN: 151990 Hom.: 21314 Cov.: 33

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.449

GnomAD2 exomes AF: 0.361 AC: 89446 AN: 247438 AF XY: 0.353

Gnomad AFR exome AF: 0.843

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.205

Gnomad FIN exome AF: 0.330

Gnomad NFE exome AF: 0.376

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.371 AC: 542153 AN: 1460254 Hom.: 106719 Cov.: 54 AF XY: 0.367 AC XY: 266836 AN XY: 726402

African (AFR) AF: 0.853 AC: 28523 AN: 33454

American (AMR) AF: 0.275 AC: 12230 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 10638 AN: 26104

East Asian (EAS) AF: 0.168 AC: 6664 AN: 39658

South Asian (SAS) AF: 0.268 AC: 23074 AN: 86152

European-Finnish (FIN) AF: 0.331 AC: 17540 AN: 52936

Middle Eastern (MID) AF: 0.423 AC: 2442 AN: 5768

European-Non Finnish (NFE) AF: 0.376 AC: 417622 AN: 1111302

Other (OTH) AF: 0.388 AC: 23420 AN: 60338

GnomAD4 genome AF: 0.485 AC: 73779 AN: 152108 Hom.: 21364 Cov.: 33 AF XY: 0.474 AC XY: 35245 AN XY: 74352

African (AFR) AF: 0.825 AC: 34239 AN: 41516

American (AMR) AF: 0.338 AC: 5169 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1470 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1067 AN: 5170

South Asian (SAS) AF: 0.260 AC: 1250 AN: 4812

European-Finnish (FIN) AF: 0.339 AC: 3586 AN: 10578

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25489 AN: 67972

Other (OTH) AF: 0.446 AC: 941 AN: 2108

Alfa AF: 0.407 Hom.: 57661

Bravo AF: 0.503

TwinsUK AF: 0.375 AC: 1390

ALSPAC AF: 0.373 AC: 1439

ESP6500AA AF: 0.824 AC: 3630

ESP6500EA AF: 0.386 AC: 3320

ExAC AF: 0.371 AC: 45035

Asia WGS AF: 0.285 AC: 992 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.050	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N
PhyloP100		2.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.12
Sift	Benign	0.79	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.022
MutPred		0.10		Gain of sheet (P = 0.0028)
MPC		0.26
ClinPred		0.0095	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1671021; hg19: chr17-73565171; COSMIC: COSV51350886; COSMIC: COSV51350886;