chr10-93797285-G-GAAATAGTCAGA

Variant names:

• chr10-93797285-G-GAAATAGTCAGA
• rs1554907767
• NM_005097.4:c.1158_1168dupAATAGTCAGAA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_005097.4(LGI1):​c.1158_1168dupAATAGTCAGAA​(p.Thr390LysfsTer2) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T390T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.42
• Publications: 0 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)

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PP5: Variant 10-93797285-G-GAAATAGTCAGA is Pathogenic according to our data. Variant chr10-93797285-G-GAAATAGTCAGA is described in ClinVar as Pathogenic. ClinVar VariationId is 533337.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1158_1168dupAATAGTCAGAA	p.Thr390LysfsTer2	frameshift stop_gained	Exon 8 of 8	NP_005088.1
	LGI1	NM_001308276.2		c.1014_1024dupAATAGTCAGAA	p.Thr342LysfsTer2	frameshift stop_gained	Exon 6 of 6	NP_001295205.1
	LGI1	NR_131777.2		n.1295_1305dupAATAGTCAGAA		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGI1	ENST00000371418.9	TSL:1 MANE Select	c.1158_1168dupAATAGTCAGAA	p.Thr390LysfsTer2	frameshift stop_gained	Exon 8 of 8	ENSP00000360472.4
	LGI1	ENST00000626307.1	TSL:1	n.5073_5083dupAATAGTCAGAA		non_coding_transcript_exon	Exon 3 of 3
	LGI1	ENST00000627420.2	TSL:1	n.*867_*877dupAATAGTCAGAA		non_coding_transcript_exon	Exon 6 of 6	ENSP00000487116.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal dominant epilepsy with auditory features (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554907767; hg19: chr10-95557042;