rs63750412

Variant names:

• chr17-44352132-C-T
• rs63750412
• NM_002087.4:c.1297C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-44352132-C-T
• chr17-44352132-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002087.4(GRN):​c.1297C>T​(p.Arg433Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,822 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R433Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (58 hom.)
• Consequence: GRN NM_002087.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.819
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036028922).
• BP6: Variant 17-44352132-C-T is Benign according to our data. Variant chr17-44352132-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 98180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.005 (761/152272) while in subpopulation NFE AF = 0.00338 (230/68004). AF 95% confidence interval is 0.00302. There are 11 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

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.1297C>T	p.Arg433Trp	missense	Exon 11 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.1297C>T	p.Arg433Trp	missense	Exon 11 of 13	ENSP00000053867.2	P28799-1
	GRN	ENST00000900927.1		c.1297C>T	p.Arg433Trp	missense	Exon 11 of 13	ENSP00000570986.1
	GRN	ENST00000900929.1		c.1297C>T	p.Arg433Trp	missense	Exon 12 of 14	ENSP00000570988.1

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 761 AN: 152154 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00548 AC: 1377 AN: 251108 AF XY: 0.00536

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0404

Gnomad NFE exome AF: 0.00323

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00408 AC: 5958 AN: 1461550 Hom.: 58 Cov.: 33 AF XY: 0.00394 AC XY: 2867 AN XY: 727122

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26134

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

South Asian (SAS) AF: 0.00194 AC: 167 AN: 86258

European-Finnish (FIN) AF: 0.0370 AC: 1968 AN: 53178

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00318 AC: 3532 AN: 1111924

Other (OTH) AF: 0.00335 AC: 202 AN: 60384

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152272 Hom.: 11 Cov.: 33 AF XY: 0.00661 AC XY: 492 AN XY: 74468

African (AFR) AF: 0.000698 AC: 29 AN: 41550

American (AMR) AF: 0.000915 AC: 14 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.0438 AC: 465 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.00175

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00432 AC: 524

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (2)
-	-	1	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.82
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.017	D
Polyphen		0.95	P
Vest4		0.30
MVP		0.90
MPC		0.48
ClinPred		0.017	T
GERP RS		1.5
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.50
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750412; hg19: chr17-42429500; COSMIC: COSV50007726; COSMIC: COSV50007726;