rs63751006

Variant names:

• chr17-44349166-T-C
• rs63751006
• NM_002087.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_002087.4(GRN):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,750 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: "SCV003294328: Experimental studies have shown that disruption of the initiator codon affects GRN function (PMID:16862116).".

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GRN NM_002087.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.28
• Publications: 14 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 36 pathogenic variants. Next in-frame start position is after 142 codons. Genomic position: 44350302. Lost 0.238 part of the original CDS.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003294328: Experimental studies have shown that disruption of the initiator codon affects GRN function (PMID: 16862116).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44349166-T-C is Pathogenic according to our data. Variant chr17-44349166-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 16008.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2T>C	p.Met1?	start_lost	Exon 2 of 13	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.2T>C	p.Met1?	start_lost	Exon 2 of 13	ENSP00000053867.2	P28799-1
	GRN	ENST00000900927.1		c.2T>C	p.Met1?	start_lost	Exon 2 of 13	ENSP00000570986.1
	GRN	ENST00000900929.1		c.2T>C	p.Met1?	start_lost	Exon 3 of 14	ENSP00000570988.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251208 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461750 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (1)
1	-	-	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.36	D
PhyloP100		1.3
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.95		Gain of catalytic residue at M1 (P = 0.0107)
MVP		1.0
ClinPred		0.96	D
GERP RS		4.7
PromoterAI		0.082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.77
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs63751006; hg19: chr17-42426534;