rs104894167

chr10-93793207-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_005097.4(LGI1):c.695T>C(p.Leu232Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LGI1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 10-93793207-T-C is Pathogenic according to our data. Variant chr10-93793207-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5437.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI1	NM_005097.4	c.695T>C	p.Leu232Pro	missense_variant	7/8	ENST00000371418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI1	ENST00000371418.9	c.695T>C	p.Leu232Pro	missense_variant	7/8	1	NM_005097.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epilepsy, familial temporal lobe, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.5	M;.;.;.;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.1	D;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;.;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.85
MutPred		0.87		Gain of disorder (P = 0.0169);.;.;Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.96

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: rs104894167; hg19: chr10-95552964;