17-44349572-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002087.4(GRN):c.264+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,786 control chromosomes in the GnomAD database, including 19,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 4235 hom., cov: 33)

Exomes 𝑓: 0.13 ( 15627 hom. )

Consequence

GRN
NM_002087.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.99

Publications

28 publications found

Variant links:

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

GRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 17-44349572-G-A is Benign according to our data. Variant chr17-44349572-G-A is described in ClinVar as Benign. ClinVar VariationId is 558916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.387 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	NM_002087.4	MANE Select	c.264+21G>A		intron	N/A	NP_002078.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GRN	ENST00000053867.8	TSL:1 MANE Select	c.264+21G>A	intron	N/A	ENSP00000053867.2
GRN	ENST00000900927.1		c.264+21G>A	intron	N/A	ENSP00000570986.1
GRN	ENST00000900929.1		c.264+21G>A	intron	N/A	ENSP00000570988.1

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30343

AN:

152128

Hom.:

4203

Cov.:

show subpopulations

Gnomad AFR

AF:

0.391

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.0898

Gnomad SAS

AF:

0.322

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.183

GnomAD2 exomes

AF:

0.159

AC:

39920

AN:

250706

AF XY:

0.163

show subpopulations

Gnomad AFR exome

AF:

0.398

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.0924

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.131

AC:

190911

AN:

1461540

Hom.:

15627

Cov.:

AF XY:

0.135

AC XY:

98345

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.405

AC:

13560

AN:

33478

American (AMR)

AF:

0.125

AC:

5611

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

3679

AN:

26134

East Asian (EAS)

AF:

0.0904

AC:

3587

AN:

39700

South Asian (SAS)

AF:

0.307

AC:

26473

AN:

86248

European-Finnish (FIN)

AF:

0.120

AC:

6411

AN:

53324

Middle Eastern (MID)

AF:

0.211

AC:

1216

AN:

5768

European-Non Finnish (NFE)

AF:

0.109

AC:

121039

AN:

1111782

Other (OTH)

AF:

0.155

AC:

9335

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

10392

20783

31175

41566

51958

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4660

9320

13980

18640

23300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.200

AC:

30424

AN:

152246

Hom.:

4235

Cov.:

AF XY:

0.201

AC XY:

14958

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.392

AC:

16259

AN:

41516

American (AMR)

AF:

0.137

AC:

2092

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

492

AN:

3470

East Asian (EAS)

AF:

0.0901

AC:

467

AN:

5186

South Asian (SAS)

AF:

0.324

AC:

1563

AN:

4828

European-Finnish (FIN)

AF:

0.123

AC:

1305

AN:

10612

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7741

AN:

68018

Other (OTH)

AF:

0.181

AC:

382

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1178

2356

3533

4711

5889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.143

Hom.:

2364

Bravo

AF:

0.203

Asia WGS

AF:

0.241

AC:

838

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (1)

Neuronal ceroid lipofuscinosis 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.019

(source)

DANN

Benign

0.46

PhyloP100

-2.0

PromoterAI

0.0068

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over