10-93793229-A-G

Variant names:

• chr10-93793229-A-G
• rs146425212
• NM_005097.4:c.717A>G

Variant summary

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

The NM_005097.4(LGI1):​c.717A>G​(p.Ile239Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. I239T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 2 publications found

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)

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=0.31452194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI1	NM_005097.4	c.717A>G	p.Ile239Met	missense_variant	Exon 7 of 8	ENST00000371418.9	NP_005088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9	c.717A>G	p.Ile239Met	missense_variant	Exon 7 of 8	1	NM_005097.4	ENSP00000360472.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;.;T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.34	N;.;.;.;N
PhyloP100		3.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N;.;.;.;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;.;D
Polyphen		0.59	P;.;P;.;P
Vest4		0.32
MutPred		0.66		Loss of stability (P = 0.0304);.;.;Loss of stability (P = 0.0304);Loss of stability (P = 0.0304);
MVP		0.56
MPC		1.2
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.69
Mutation Taster		=59/41	polymorphism

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: rs146425212; hg19: chr10-95552986;