NM_005097.4:c.758delC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2
The NM_005097.4(LGI1):c.758delC (p.Ala253ValfsTer32) variant causes a frameshift change. This is a loss-of-function variant that does not trigger NMD. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars).
Frequency
Genomes: not found (cov: 32)
Consequence
LGI1
NM_005097.4 frameshift
NM_005097.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.17
Publications
2 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 featuresInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen
- epilepsy, familial temporal lobe, 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
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new If you want to explore the variant's impact on the transcript NM_005097.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Classification was made for transcript:
Our verdict: Pathogenic. The variant received 10 points.
| Apply | Criterion Code & Title / Strength | Rationale / Clinical Context | |
|---|---|---|---|
| PVS1Null variant in LOF gene | Non-NMD frameshift: ≥4 downstream pathogenic — very strong evidence preserved (PVS1); Frameshift (exon 7 of 8) at amino acid 253 of 557; NMD not predicted. 34 pathogenic variants downstream support preserved loss-of-function impact. A new stop codon is introduced in the shifted frame, truncating the protein to ~283 amino acids (274 amino acids lost). | ||
| PM2Absent/extremely low in population databases | Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate. |
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_005097.4. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
LGI1 | MANE Select | c.758delC p.Ala253ValfsTer32 | frameshift | Exon 7 of 8 | Prot: NP_005088.1 UniProt: | |
LGI1 | c.614delC p.Ala205ValfsTer32 | frameshift | Exon 5 of 6 | Prot: NP_001295205.1 UniProt: | ||
LGI1 | c.758delC p.Ala253ValfsTer29 | frameshift | Exon 7 of 8 | Prot: NP_001295204.1 UniProt: |
HGVSc / HGVSpc.758delCp.Ala253ValfsTer32
Exon rankExon 7 of 8
frameshift
Prot: NP_005088.1UniProt: A0A0S2Z4S7 O95970-1
HGVSc / HGVSpc.614delCp.Ala205ValfsTer32
Exon rankExon 5 of 6
frameshift
Prot: NP_001295205.1UniProt: O95970-3
HGVSc / HGVSpc.758delCp.Ala253ValfsTer29
Exon rankExon 7 of 8
frameshift
Prot: NP_001295204.1UniProt: A0A0S2Z4X3 O95970-2
Ensembl Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
LGI1 | TSL:1MANE Select | c.758delC p.Ala253ValfsTer32 | frameshift | Exon 7 of 8 | Prot: ENSP00000360472.4 UniProt: | |
LGI1 | TSL:1 | c.758delC p.Ala253ValfsTer29 | frameshift | Exon 7 of 8 | Prot: ENSP00000360467.3 UniProt: | |
LGI1 | TSL:1 | n.*467delC | 3_prime_UTR | Exon 5 of 6 | Prot: ENSP00000487116.1 UniProt: |
HGVSc / HGVSpc.758delCp.Ala253ValfsTer32
Exon rankExon 7 of 8
frameshift
Prot: ENSP00000360472.4UniProt: O95970-1
HGVSc / HGVSpc.758delCp.Ala253ValfsTer29
Exon rankExon 7 of 8
frameshift
Prot: ENSP00000360467.3UniProt: O95970-2
Frequencies
Allele frequencies (AF), counts (AC/AN), homozygotes and coverage
Common (AF > 0.05 / Hom > 5)
Rare (AF ≤ 0.0001 / Hom ≤ 1)
| Source / population | AF | AC | Hom | AN | Coverage |
|---|---|---|---|---|---|
Global population databases 3 sources | |||||
GnomAD3 genomes | Cov:32 | ||||
GnomAD4 exome | Cov:31 | ||||
GnomAD4 genome | Cov:32 | ||||
Showing 3 sources
ClinVar
ClinVar submissions
View on ClinVar Significance:not provided
Revision:no classification provided
Pathogenic
VUS
Benign
Condition
-
-
-
Epilepsy, familial temporal lobe, 1 (1)
Computational Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
Mutation Taster | N/A | 8/192 | disease causing (ClinVar) |
PhyloP100 | Uncertain | 6.2 |
Showing 2 of 2 scores
Splicing Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
SpliceAI score (max) | Benign | 0.0 | Details are displayed if max score is > 0.2 |
Showing 1 of 1 scores
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
MaveDB functional evidence
No MaveDB functional evidence found for this variant.
Publications
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Other links and lift over
dbSNP: rs797044997 ;
hg19: chr10-95553026;