rs63751294
Variant summary
Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong
The NM_002087.4(GRN):c.1477C>T(p.Arg493*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000322383: Published functional studies demonstrate a damaging effect (Fujita et al., 2018)". Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002087.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- frontotemporal dementia and/or amyotrophic lateral sclerosisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- neuronal ceroid lipofuscinosisInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- GRN-related frontotemporal lobar degeneration with Tdp43 inclusionsInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- neuronal ceroid lipofuscinosis 11Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp, Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 20 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002087.4. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GRN | TSL:1 MANE Select | c.1477C>T | p.Arg493* | stop_gained | Exon 12 of 13 | ENSP00000053867.2 | P28799-1 | ||
| GRN | c.1477C>T | p.Arg493* | stop_gained | Exon 12 of 13 | ENSP00000570986.1 | ||||
| GRN | c.1477C>T | p.Arg493* | stop_gained | Exon 13 of 14 | ENSP00000570988.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251110 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461638Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 727158 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 33
ClinVar
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at