rs202204627

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2

The NM_005097.4(LGI1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,614,034 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 7 hom. )

Consequence

LGI1
NM_005097.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.78

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
epilepsy, familial temporal lobe, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

LGI1 links:

ENSG00000303320 (HGNC:):

ENSG00000303320 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 9 codons. Genomic position: 93758169. Lost 0.015 part of the original CDS.

BP6

Variant 10-93758145-A-G is Benign according to our data. Variant chr10-93758145-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 415035.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000775 (118/152342) while in subpopulation EAS AF = 0.000965 (5/5180). AF 95% confidence interval is 0.00038. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI1	NM_005097.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	ENST00000371418.9	NP_005088.1	O95970-1A0A0S2Z4S7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	1	NM_005097.4	ENSP00000360472.4		O95970-1

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00734

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00105

AC:

264

AN:

251302

AF XY:

0.000891

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00693

Gnomad NFE exome

AF:

0.000871

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000462

AC:

675

AN:

1461692

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

333

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00749

AC:

400

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000187

AC:

208

AN:

1111854

Other (OTH)

AF:

0.000878

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152342

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00734

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000620

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LGI1: BS1 -

Oct 16, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26993267) -

Epilepsy, familial temporal lobe, 1

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Nov 08, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant epilepsy with auditory features

Benign:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LGI1-related disorder

Benign:1

Aug 26, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

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

Eigen

Benign

-0.12

Eigen_PC

Benign

0.022

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.90

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.012

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

MetaSVM

Benign

-0.74

PhyloP100

1.8

PROVEAN

Benign

-0.48

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

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.0

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

Vest4

0.35

MVP

0.89

ClinPred

0.18

GERP RS

4.7

PromoterAI

0.031

Neutral

(source)

Varity_R

0.90

gMVP

0.68

Mutation Taster

=105/95

polymorphism

(source)

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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rs202204627

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over