10-93758206-A-G

Position:

• chr10-93758206-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005097.4(LGI1):​c.62A>G​(p.Tyr21Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y21H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI1	NM_005097.4	c.62A>G	p.Tyr21Cys	missense_variant	1/8	ENST00000371418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI1	ENST00000371418.9	c.62A>G	p.Tyr21Cys	missense_variant	1/8	1	NM_005097.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2024

The c.62A>G (p.Y21C) alteration is located in exon 1 (coding exon 1) of the LGI1 gene. This alteration results from a A to G substitution at nucleotide position 62, causing the tyrosine (Y) at amino acid position 21 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;.;.;.;.;T;T;.
Eigen	Benign	-0.0099
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.87	D;T;.;.;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.69	N;.;.;.;N;.;.;N
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.0	N;.;.;.;.;.;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.094	T;.;.;.;.;.;.;D
Sift4G	Benign	0.093	T;T;T;T;T;.;T;T
Polyphen		0.56	P;.;.;.;P;.;.;P
Vest4		0.38
MutPred		0.67		Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);
MVP		0.85
MPC		1.6
ClinPred		0.52	D
GERP RS		4.7
Varity_R		0.11
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-95517963;