dbSNP rs34424835: GRN:c.350-50_350-47dupGTCA (chr17-44350176-G-GAGTC) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_002087.4(GRN):c.350-50_350-47dupGTCA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8862 hom., cov: 0)

Exomes 𝑓: 0.25 ( 37274 hom. )

Consequence

GRN
NM_002087.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.175

Publications

9 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 -16 ACMG points.

BP6

Variant 17-44350176-G-GAGTC is Benign according to our data. Variant chr17-44350176-G-GAGTC is described in ClinVar as Benign. ClinVar VariationId is 803426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4 link	c.350-50_350-47dupGTCA		intron_variant	Intron 4 of 12	ENST00000053867.8	NP_002078.1	P28799-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 link	c.350-52_350-51insAGTC		intron_variant	Intron 4 of 12	1	NM_002087.4	ENSP00000053867.2		P28799-1

Frequencies

GnomAD3 genomes

AF:

0.321

AC:

48705

AN:

151572

Hom.:

8850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.481

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.247

Gnomad ASJ

AF:

0.355

Gnomad EAS

AF:

0.495

Gnomad SAS

AF:

0.327

Gnomad FIN

AF:

0.298

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.232

Gnomad OTH

AF:

0.309

GnomAD4 exome

AF:

0.248

AC:

267622

AN:

1078078

Hom.:

37274

Cov.:

AF XY:

0.251

AC XY:

139058

AN XY:

553102

show subpopulations

African (AFR)

AF:

0.467

AC:

12012

AN:

25700

American (AMR)

AF:

0.231

AC:

10229

AN:

44248

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

8374

AN:

23630

East Asian (EAS)

AF:

0.507

AC:

19156

AN:

37768

South Asian (SAS)

AF:

0.312

AC:

24435

AN:

78356

European-Finnish (FIN)

AF:

0.300

AC:

15934

AN:

53092

Middle Eastern (MID)

AF:

0.327

AC:

1643

AN:

5032

European-Non Finnish (NFE)

AF:

0.213

AC:

162785

AN:

762614

Other (OTH)

AF:

0.274

AC:

13054

AN:

47638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

10830

21659

32489

43318

54148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4618

9236

13854

18472

23090

<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:

0.321

AC:

48741

AN:

151690

Hom.:

8862

Cov.:

AF XY:

0.323

AC XY:

23924

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.481

AC:

19825

AN:

41240

American (AMR)

AF:

0.247

AC:

3765

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.355

AC:

1228

AN:

3464

East Asian (EAS)

AF:

0.494

AC:

2544

AN:

5148

South Asian (SAS)

AF:

0.327

AC:

1574

AN:

4816

European-Finnish (FIN)

AF:

0.298

AC:

3141

AN:

10552

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.232

AC:

15768

AN:

67894

Other (OTH)

AF:

0.308

AC:

647

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1595

3191

4786

6382

7977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.286

Hom.:

732

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.17

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over