17-44346188-C-T

Variant names:

• chr17-44346188-C-T
• rs2879096
• NM_002087.4:c.-8+854C>T

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+854C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 154,108 control chromosomes in the GnomAD database, including 6,409 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 0.28 (6284 hom., cov: 32)
  • Exomes 𝑓: 0.32 (125 hom.)
• Consequence: GRN NM_002087.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.620
• Publications: 10 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), G2P, Ambry Genetics, Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

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.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	NM_002087.4	MANE Select	c.-8+854C>T		intron	N/A	NP_002078.1	P28799-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	ENST00000053867.8	TSL:1 MANE Select	c.-8+854C>T		intron	N/A	ENSP00000053867.2	P28799-1
	GRN	ENST00000918286.1		c.-48C>T		5_prime_UTR	Exon 2 of 14	ENSP00000588345.1
	GRN	ENST00000944507.1		c.-48C>T		5_prime_UTR	Exon 3 of 15	ENSP00000614566.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42115 AN: 151948 Hom.: 6280 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.322 AC: 657 AN: 2042 Hom.: 125 Cov.: 0 AF XY: 0.315 AC XY: 354 AN XY: 1124

African (AFR) AF: 0.250 AC: 10 AN: 40

American (AMR) AF: 0.393 AC: 11 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 13 AN: 50

East Asian (EAS) AF: 0.660 AC: 165 AN: 250

South Asian (SAS) AF: 0.563 AC: 9 AN: 16

European-Finnish (FIN) AF: 0.367 AC: 105 AN: 286

Middle Eastern (MID) AF: 0.214 AC: 3 AN: 14

European-Non Finnish (NFE) AF: 0.252 AC: 316 AN: 1254

Other (OTH) AF: 0.240 AC: 25 AN: 104

GnomAD4 genome AF: 0.277 AC: 42131 AN: 152066 Hom.: 6284 Cov.: 32 AF XY: 0.287 AC XY: 21298 AN XY: 74324

African (AFR) AF: 0.233 AC: 9685 AN: 41510

American (AMR) AF: 0.309 AC: 4718 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3466

East Asian (EAS) AF: 0.584 AC: 3012 AN: 5160

South Asian (SAS) AF: 0.429 AC: 2061 AN: 4808

European-Finnish (FIN) AF: 0.328 AC: 3469 AN: 10574

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17566 AN: 67944

Other (OTH) AF: 0.258 AC: 544 AN: 2112

Alfa AF: 0.154 Hom.: 324

Bravo AF: 0.273

Asia WGS AF: 0.492 AC: 1710 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.1
DANN	Benign	0.94
PhyloP100		-0.62
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: rs2879096; hg19: chr17-42423556;