10-93758199-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005097.4(LGI1):c.55A>G(p.Ile19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

Genes affected

LGI1 (HGNC:6572): (leucine rich glioma inactivated 1) This gene encodes a member of the secreted leucine-rich repeat (LRR) superfamily and shares homology with members of the SLIT protein family. The encoded protein may regulate the activity of voltage-gated potassium channels and may be involved in neuronal growth regulation and cell survival. This gene is rearranged as a result of translocations in glioblastoma cell lines, and it is frequently down-regulated or rearranged in malignant gliomas. Mutations in this gene result in autosomal dominant lateral temporal epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LGI1
• BP4: Computational evidence support a benign effect (MetaRNN=0.15830007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI1	NM_005097.4	c.55A>G	p.Ile19Val	missense_variant	1/8	ENST00000371418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI1	ENST00000371418.9	c.55A>G	p.Ile19Val	missense_variant	1/8	1	NM_005097.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant epilepsy with auditory features Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2021

This sequence change replaces isoleucine with valine at codon 19 of the LGI1 protein (p.Ile19Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with LGI1-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T;.;.;.;.;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.92	D;D;.;.;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.76	N;.;.;.;N;.;.;N
MutationTaster	Benign	0.66	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.12	N;.;.;.;.;.;.;N
REVEL	Benign	0.077
Sift	Benign	0.48	T;.;.;.;.;.;.;T
Sift4G	Benign	0.42	T;T;T;T;T;.;T;T
Polyphen		0.019	B;.;.;.;B;.;.;B
Vest4		0.093
MutPred		0.32		Gain of MoRF binding (P = 0.1004);Gain of MoRF binding (P = 0.1004);Gain of MoRF binding (P = 0.1004);Gain of MoRF binding (P = 0.1004);Gain of MoRF binding (P = 0.1004);Gain of MoRF binding (P = 0.1004);Gain of MoRF binding (P = 0.1004);Gain of MoRF binding (P = 0.1004);
MVP		0.56
MPC		0.62
ClinPred		0.48	T
GERP RS		4.7
Varity_R		0.070
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs2059584229; hg19: chr10-95517956; COSMIC: COSV65057453; COSMIC: COSV65057453;