chr17-44350570-CAG-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000053867.8(GRN):c.592_593del(p.Arg198GlyfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
GRN
ENST00000053867.8 frameshift
ENST00000053867.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0430
Genes affected
GRN (HGNC:4601): (granulin precursor) Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-44350570-CAG-C is Pathogenic according to our data. Variant chr17-44350570-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 447475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44350570-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRN | NM_002087.4 | c.592_593del | p.Arg198GlyfsTer19 | frameshift_variant | 6/13 | ENST00000053867.8 | NP_002078.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GRN | ENST00000053867.8 | c.592_593del | p.Arg198GlyfsTer19 | frameshift_variant | 6/13 | 1 | NM_002087.4 | ENSP00000053867 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 26, 2023 | PM2_moderate, PS4_moderate, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 03, 2017 | - - |
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 11, 2023 | This sequence change creates a premature translational stop signal (p.Arg198Glyfs*19) in the GRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with frontotemporal dementia, frontotemporal lobar degeneration, primary progressive aphasia, and/or Alzheimer's disease (PMID: 20142524, 21482928, 23383383, 33980708). ClinVar contains an entry for this variant (Variation ID: 447475). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at