10-93758178-G-T

Position:

chr10-93758178-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_005097.4(LGI1):c.34G>T(p.Ala12Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A12T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

LGI1
NM_005097.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.04

Variant links:

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]

LGI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LGI1. . Gene score misZ 2.7809 (greater than the threshold 3.09). Trascript score misZ 3.4769 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, familial temporal lobe, 1, autosomal dominant epilepsy with auditory features.

BP4

Computational evidence support a benign effect (MetaRNN=0.14188787).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000547 (8/1461874) while in subpopulation AMR AF= 0.000179 (8/44720). AF 95% confidence interval is 0.0000886. There are 0 homozygotes in gnomad4_exome. There are 6 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 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI1	NM_005097.4 linkuse as main transcript	c.34G>T	p.Ala12Ser	missense_variant	1/8	ENST00000371418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI1	ENST00000371418.9 linkuse as main transcript	c.34G>T	p.Ala12Ser	missense_variant	1/8	1	NM_005097.4	P1	O95970-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251400

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000547

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant epilepsy with auditory features

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

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. ClinVar contains an entry for this variant (Variation ID: 284206). This variant has not been reported in the literature in individuals affected with LGI1-related conditions. This variant is present in population databases (rs770065197, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the LGI1 protein (p.Ala12Ser). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.23

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

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.0034

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.90

L;.;.;.;L;.;.;L

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.45

N;.;.;.;.;.;.;N

REVEL

Benign

0.10

Sift

Benign

0.20

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

Sift4G

Benign

0.23

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

Polyphen

0.0020

B;.;.;.;B;.;.;B

Vest4

0.26

MutPred

0.46

Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);

MVP

0.53

MPC

0.83

ClinPred

0.13

GERP RS

3.7

Varity_R

0.14

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over