17-44351080-CTG-CTGTG

Variant names:

• chr17-44351080-C-CTG
• rs63751035
• NM_002087.4:c.759_760dupTG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002087.4(GRN):​c.759_760dupTG​(p.Asp254ValfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GRN NM_002087.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -2.09
• Publications: 3 publications found

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]

GRN Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• neuronal ceroid lipofuscinosis 11

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 17-44351080-C-CTG is Pathogenic according to our data. Variant chr17-44351080-C-CTG is described in ClinVar as Pathogenic. ClinVar VariationId is 599610.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4	c.759_760dupTG	p.Asp254ValfsTer3	frameshift_variant	Exon 8 of 13	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.759_760dupTG	p.Asp254ValfsTer3	frameshift_variant	Exon 8 of 13	1	NM_002087.4	ENSP00000053867.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461706 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia Pathogenic:1

Feb 01, 2017

Human Genetics Group at Institute of Prion Diseases London, University College London

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This result confirms the diagnosis of a GRN-related dementia. This 2-bp duplication in granulin exon 8 causes a frameshift and a premature STOP, 3 codons downstream. Although this specific sequence change has not been previously reported, several pathogenic frameshift mutations in GRN have been previously described in the literature1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs63751035; hg19: chr17-42428448;