chr17-75558180-A-C

Variant names:

• chr17-75558180-A-C
• rs149829375
• NM_001031803.2:c.199A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001031803.2(LLGL2):​c.199A>C​(p.Met67Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. M67V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LLGL2 NM_001031803.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.87
• 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: 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=0.41592634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLGL2	NM_001031803.2	c.199A>C	p.Met67Leu	missense_variant	Exon 4 of 26	ENST00000392550.8	NP_001026973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LLGL2	ENST00000392550.8	c.199A>C	p.Met67Leu	missense_variant	Exon 4 of 26	1	NM_001031803.2	ENSP00000376333.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461498 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727090

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.019	T;.;.;T;.;T;.;T;T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D;.;D;D;D;D;D;D;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	.;M;M;M;M;.;.;.;.;.
PhyloP100		6.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.84	.;N;N;N;.;.;.;.;.;.
REVEL	Benign	0.14
Sift	Benign	0.13	.;T;T;T;.;.;.;.;.;.
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T
Polyphen		0.050, 0.17, 0.11	.;B;B;B;B;.;.;.;.;.
Vest4		0.54, 0.55, 0.55, 0.55, 0.54
MutPred		0.40		Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);.;
MVP		0.84
MPC		0.21
ClinPred		0.66	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.42

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: rs149829375; hg19: chr17-73554261;