10-93758178-G-T

Position:

• chr10-93758178-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_005097.4(LGI1):​c.34G>T​(p.Ala12Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.04

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14188787).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000547 (8/1461874) while in subpopulation AMR AF= 0.000179 (8/44720). AF 95% confidence interval is 0.0000886. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LGI1	NM_005097.4	c.34G>T	p.Ala12Ser	missense_variant	1/8	ENST00000371418.9	NP_005088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9	c.34G>T	p.Ala12Ser	missense_variant	1/8	1	NM_005097.4	ENSP00000360472.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251400 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant epilepsy with auditory features Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 284206). This variant has not been reported in the literature in individuals affected with LGI1-related conditions. This variant is present in population databases (rs770065197, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the LGI1 protein (p.Ala12Ser). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;.;.;.;.;T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.0034
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D;T;.;.;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.90	L;.;.;.;L;.;.;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.45	N;.;.;.;.;.;.;N
REVEL	Benign	0.10
Sift	Benign	0.20	T;.;.;.;.;.;.;T
Sift4G	Benign	0.23	T;T;T;T;T;.;T;T
Polyphen		0.0020	B;.;.;.;B;.;.;B
Vest4		0.26
MutPred		0.46		Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);
MVP		0.53
MPC		0.83
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.41

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: rs770065197; hg19: chr10-95517935;