10-93758200-T-C

Position:

• chr10-93758200-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005097.4(LGI1):​c.56T>C​(p.Ile19Thr) 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. 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. I19V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.31794232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI1	NM_005097.4	c.56T>C	p.Ile19Thr	missense_variant	1/8	ENST00000371418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI1	ENST00000371418.9	c.56T>C	p.Ile19Thr	missense_variant	1/8	1	NM_005097.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

Jul 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.21	T;.;.;.;.;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.94	D;D;.;.;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L;.;.;.;L;.;.;L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.36	N;.;.;.;.;.;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.46	T;.;.;.;.;.;.;T
Sift4G	Benign	0.51	T;T;T;T;T;.;T;T
Polyphen		0.18	B;.;.;.;B;.;.;P
Vest4		0.52
MutPred		0.57		Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);
MVP		0.92
MPC		1.0
ClinPred		0.52	D
GERP RS		4.7
Varity_R		0.087
gMVP		0.38

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: rs1589746991; hg19: chr10-95517957;