chr10-93758268-T-C

Variant names:

• chr10-93758268-T-C
• rs797044996
• NM_005097.4:c.124T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005097.4(LGI1):​c.124T>C​(p.Cys42Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C42G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.03
• Publications: 11 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)

ENSG00000303320 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005097.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI1	NM_005097.4	MANE Select	c.124T>C	p.Cys42Arg	missense	Exon 1 of 8	NP_005088.1
	LGI1	NM_001308276.2		c.124T>C	p.Cys42Arg	missense	Exon 1 of 6	NP_001295205.1
	LGI1	NM_001308275.2		c.124T>C	p.Cys42Arg	missense	Exon 1 of 8	NP_001295204.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI1	ENST00000371418.9	TSL:1 MANE Select	c.124T>C	p.Cys42Arg	missense	Exon 1 of 8	ENSP00000360472.4
	LGI1	ENST00000371413.4	TSL:1	c.124T>C	p.Cys42Arg	missense	Exon 1 of 8	ENSP00000360467.3
	LGI1	ENST00000627420.2	TSL:1	n.124T>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000487116.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Epilepsy, familial temporal lobe, 1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.95
MutPred		0.96		Gain of disorder (P = 0.0339)
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		0.024	Neutral
Varity_R		0.97
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797044996; hg19: chr10-95518025;