17-44347231-G-C

Variant names:

• chr17-44347231-G-C
• rs4792938
• NM_002087.4:c.-8+1897G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002087.4(GRN):​c.-8+1897G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 152,084 control chromosomes in the GnomAD database, including 18,001 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (18001 hom., cov: 31)
• Consequence: GRN NM_002087.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.95
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4	c.-8+1897G>C		intron_variant	Intron 1 of 12	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.-8+1897G>C		intron_variant	Intron 1 of 12	1	NM_002087.4	ENSP00000053867.2

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70092 AN: 151966 Hom.: 17947 Cov.: 31

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.438

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.462 AC: 70206 AN: 152084 Hom.: 18001 Cov.: 31 AF XY: 0.472 AC XY: 35093 AN XY: 74356

African (AFR) AF: 0.611 AC: 25338 AN: 41476

American (AMR) AF: 0.497 AC: 7599 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1080 AN: 3470

East Asian (EAS) AF: 0.915 AC: 4732 AN: 5172

South Asian (SAS) AF: 0.617 AC: 2975 AN: 4822

European-Finnish (FIN) AF: 0.432 AC: 4573 AN: 10576

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22649 AN: 67968

Other (OTH) AF: 0.445 AC: 939 AN: 2112

Alfa AF: 0.396 Hom.: 1642

Bravo AF: 0.475

Asia WGS AF: 0.767 AC: 2665 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.60
DANN	Benign	0.36
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4792938; hg19: chr17-42424599;