dbSNP rs1247821190: LLGL2:p.His33Pro (chr17-75556068-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001031803.2(LLGL2):c.98A>C(p.His33Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H33R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LLGL2
NM_001031803.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.27

Publications

0 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]

LLGL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL2	NM_001031803.2 link	c.98A>C	p.His33Pro	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
LLGL2	ENST00000392550.8 link	c.98A>C	p.His33Pro	missense_variant	Exon 3 of 26	1	NM_001031803.2	ENSP00000376333.4		Q6P1M3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456976

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725108

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111922

Other (OTH)

AF:

0.00

AC:

AN:

60348

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.11

T;.;.;T;.;T;.;T;T;T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;T;.;T;T;D;T;D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

.;M;M;M;M;.;.;.;.;.;.

PhyloP100

9.3

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.9

.;D;D;D;.;.;.;.;.;.;.

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0030

.;D;D;D;.;.;.;.;.;.;.

Sift4G

Uncertain

0.012

D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0, 0.97

.;D;D;D;D;.;.;.;.;.;.

Vest4

0.80, 0.78, 0.80, 0.78, 0.80

MutPred

0.41

Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);Gain of catalytic residue at P32 (P = 0.0186);.;

MVP

0.95

MPC

0.99

ClinPred

0.99

GERP RS

4.7

Varity_R

0.85

gMVP

0.89

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over