10-93758191-T-G

Position:

• chr10-93758191-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_005097.4(LGI1):​c.47T>G​(p.Leu16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000048 (0 hom.)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.26

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26348704).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000479 (7/1461878) while in subpopulation EAS AF= 0.000151 (6/39700). AF 95% confidence interval is 0.0000651. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGI1	NM_005097.4	c.47T>G	p.Leu16Arg	missense_variant	1/8	ENST00000371418.9	NP_005088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9	c.47T>G	p.Leu16Arg	missense_variant	1/8	1	NM_005097.4	ENSP00000360472.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251418 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS 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: 0.00000479 AC: 7 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant epilepsy with auditory features Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2023

ClinVar contains an entry for this variant (Variation ID: 1494056). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with LGI1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 16 of the LGI1 protein (p.Leu16Arg). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

LGI1: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T;.;.;.;.;T;T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.87	D;T;.;.;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.34	N;.;.;.;N;.;.;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.28	N;.;.;.;.;.;.;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D;.;.;.;.;.;.;D
Sift4G	Uncertain	0.055	T;D;T;D;T;.;D;D
Polyphen		0.019	B;.;.;.;B;.;.;P
Vest4		0.55
MutPred		0.69		Loss of catalytic residue at L16 (P = 0.0141);Loss of catalytic residue at L16 (P = 0.0141);Loss of catalytic residue at L16 (P = 0.0141);Loss of catalytic residue at L16 (P = 0.0141);Loss of catalytic residue at L16 (P = 0.0141);Loss of catalytic residue at L16 (P = 0.0141);Loss of catalytic residue at L16 (P = 0.0141);Loss of catalytic residue at L16 (P = 0.0141);
MVP		0.86
MPC		1.3
ClinPred		0.20	T
GERP RS		4.7
Varity_R		0.30
gMVP		0.43

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: rs1234339369; hg19: chr10-95517948;