chr17-44350262-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002087.4(GRN):c.384T>C(p.Asp128Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 1,613,744 control chromosomes in the GnomAD database, including 2,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 222 hom., cov: 32)

Exomes 𝑓: 0.036 ( 2410 hom. )

Consequence

GRN
NM_002087.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: -2.70

Publications

24 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), G2P, Ambry Genetics, Genomics England PanelApp, Orphanet

GRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.003).

BP6

Variant 17-44350262-T-C is Benign according to our data. Variant chr17-44350262-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 98137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.7 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.234 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.384T>C	p.Asp128Asp	synonymous	Exon 5 of 13	NP_002078.1	P28799-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRN	ENST00000053867.8	TSL:1 MANE Select	c.384T>C	p.Asp128Asp	synonymous	Exon 5 of 13	ENSP00000053867.2	P28799-1
GRN	ENST00000918287.1		c.299T>C	p.Ile100Thr	missense	Exon 4 of 12	ENSP00000588346.1
GRN	ENST00000900927.1		c.384T>C	p.Asp128Asp	synonymous	Exon 5 of 13	ENSP00000570986.1

Frequencies

GnomAD3 genomes

AF:

0.0318

AC:

4837

AN:

152036

Hom.:

224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00703

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0426

Gnomad ASJ

AF:

0.0734

Gnomad EAS

AF:

0.247

Gnomad SAS

AF:

0.0877

Gnomad FIN

AF:

0.00632

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0264

Gnomad OTH

AF:

0.0308

GnomAD2 exomes

AF:

0.0514

AC:

12919

AN:

251478

AF XY:

0.0518

show subpopulations

Gnomad AFR exome

AF:

0.00597

Gnomad AMR exome

AF:

0.0587

Gnomad ASJ exome

AF:

0.0654

Gnomad EAS exome

AF:

0.248

Gnomad FIN exome

AF:

0.00591

Gnomad NFE exome

AF:

0.0258

Gnomad OTH exome

AF:

0.0344

GnomAD4 exome

AF:

0.0364

AC:

53149

AN:

1461590

Hom.:

2410

Cov.:

AF XY:

0.0377

AC XY:

27426

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.00487

AC:

163

AN:

33480

American (AMR)

AF:

0.0565

AC:

2525

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0638

AC:

1666

AN:

26128

East Asian (EAS)

AF:

0.273

AC:

10854

AN:

39694

South Asian (SAS)

AF:

0.0762

AC:

6568

AN:

86234

European-Finnish (FIN)

AF:

0.00635

AC:

339

AN:

53416

Middle Eastern (MID)

AF:

0.0397

AC:

229

AN:

5768

European-Non Finnish (NFE)

AF:

0.0254

AC:

28216

AN:

1111760

Other (OTH)

AF:

0.0429

AC:

2589

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3066

6131

9197

12262

15328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1264

2528

3792

5056

6320

<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:

0.0317

AC:

4827

AN:

152154

Hom.:

222

Cov.:

AF XY:

0.0331

AC XY:

2459

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00701

AC:

291

AN:

41522

American (AMR)

AF:

0.0426

AC:

652

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0734

AC:

255

AN:

3472

East Asian (EAS)

AF:

0.245

AC:

1266

AN:

5160

South Asian (SAS)

AF:

0.0874

AC:

421

AN:

4818

European-Finnish (FIN)

AF:

0.00632

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0264

AC:

1795

AN:

67974

Other (OTH)

AF:

0.0314

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

233

465

698

930

1163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0324

Hom.:

428

Bravo

AF:

0.0310

Asia WGS

AF:

0.131

AC:

459

AN:

3478

EpiCase

AF:

0.0296

EpiControl

AF:

0.0277

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (5)

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 (2)

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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.45

(source)

DANN

Benign

0.38

PhyloP100

-2.7

PromoterAI

0.0026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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