NM_018325.5:c.870C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_018325.5(C9orf72):c.870C>T(p.Ser290Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,609,536 control chromosomes in the GnomAD database, including 36,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3437 hom., cov: 33)

Exomes 𝑓: 0.21 ( 32681 hom. )

Consequence

C9orf72
NM_018325.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.04

Publications

43 publications found

Variant links:

Genes affected

C9orf72 (HGNC:28337): (C9orf72-SMCR8 complex subunit) The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]

C9orf72 Gene-Disease associations (from GenCC):

frontotemporal dementia and/or amyotrophic lateral sclerosis 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
progressive myoclonus epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

C9orf72 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 9-27556782-G-A is Benign according to our data. Variant chr9-27556782-G-A is described in ClinVar as [Benign]. Clinvar id is 366524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5 link	c.870C>T	p.Ser290Ser	synonymous_variant	Exon 8 of 11	ENST00000380003.8	NP_060795.1	Q96LT7-1
C9orf72	NM_001256054.3 link	c.870C>T	p.Ser290Ser	synonymous_variant	Exon 8 of 11		NP_001242983.1	Q96LT7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8 link	c.870C>T	p.Ser290Ser	synonymous_variant	Exon 8 of 11	1	NM_018325.5	ENSP00000369339.3		Q96LT7-1

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31790

AN:

151996

Hom.:

3423

Cov.:

show subpopulations

Gnomad AFR

AF:

0.185

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.259

Gnomad ASJ

AF:

0.144

Gnomad EAS

AF:

0.303

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.237

AC:

59130

AN:

249814

AF XY:

0.234

show subpopulations

Gnomad AFR exome

AF:

0.183

Gnomad AMR exome

AF:

0.331

Gnomad ASJ exome

AF:

0.148

Gnomad EAS exome

AF:

0.314

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.207

Gnomad OTH exome

AF:

0.214

GnomAD4 exome

AF:

0.207

AC:

302344

AN:

1457422

Hom.:

32681

Cov.:

AF XY:

0.209

AC XY:

151382

AN XY:

725254

show subpopulations

African (AFR)

AF:

0.180

AC:

5999

AN:

33360

American (AMR)

AF:

0.319

AC:

14247

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.150

AC:

3917

AN:

26108

East Asian (EAS)

AF:

0.265

AC:

10519

AN:

39664

South Asian (SAS)

AF:

0.259

AC:

22287

AN:

86134

European-Finnish (FIN)

AF:

0.230

AC:

12295

AN:

53372

Middle Eastern (MID)

AF:

0.158

AC:

909

AN:

5758

European-Non Finnish (NFE)

AF:

0.199

AC:

220145

AN:

1108102

Other (OTH)

AF:

0.200

AC:

12026

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

10821

21642

32464

43285

54106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.209

AC:

31824

AN:

152114

Hom.:

3437

Cov.:

AF XY:

0.212

AC XY:

15738

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.185

AC:

7689

AN:

41508

American (AMR)

AF:

0.260

AC:

3968

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

498

AN:

3468

East Asian (EAS)

AF:

0.303

AC:

1565

AN:

5162

South Asian (SAS)

AF:

0.260

AC:

1254

AN:

4828

European-Finnish (FIN)

AF:

0.239

AC:

2526

AN:

10590

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.200

AC:

13618

AN:

67982

Other (OTH)

AF:

0.210

AC:

442

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1294

2589

3883

5178

6472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.205

Hom.:

15133

Bravo

AF:

0.214

Asia WGS

AF:

0.286

AC:

997

AN:

3478

EpiCase

AF:

0.191

EpiControl

AF:

0.195

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

8.2

(source)

DANN

Benign

0.71

PhyloP100

1.0

Mutation Taster

=99/1

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

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

NM_018325.5:c.870C>T

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