Genetic Variant C9orf72:c.1260-20_1260-14dupTTTTTTT (chr9-27548435-G-GAAAAAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018325.5(C9orf72):c.1260-20_1260-14dupTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0042 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00094 ( 2 hom. )

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.242

Publications

1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
progressive myoclonus epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

C9orf72 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 155 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018325.5. 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
	C9orf72	NM_018325.5	MANE Select	c.1260-20_1260-14dupTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-20_1260-14dupTTTTTTT		intron	N/A	NP_001242983.1	Q96LT7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.1260-20_1260-14dupTTTTTTT	intron	N/A	ENSP00000369339.3	Q96LT7-1
C9orf72	ENST00000619707.5	TSL:1	c.1260-20_1260-14dupTTTTTTT	intron	N/A	ENSP00000482753.1	Q96LT7-1
C9orf72	ENST00000644136.1		c.1293-20_1293-14dupTTTTTTT	intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes

AF:

0.00424

AC:

156

AN:

36766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00257

Gnomad AMI

AF:

0.00575

Gnomad AMR

AF:

0.000646

Gnomad ASJ

AF:

0.00368

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00279

Gnomad FIN

AF:

0.00258

Gnomad MID

AF:

0.0172

Gnomad NFE

AF:

0.00575

Gnomad OTH

AF:

0.00612

GnomAD4 exome

AF:

0.000941

AC:

130

AN:

138108

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

71364

show subpopulations

African (AFR)

AF:

0.000323

AC:

AN:

3100

American (AMR)

AF:

0.00194

AC:

AN:

5658

Ashkenazi Jewish (ASJ)

AF:

0.000537

AC:

AN:

3726

East Asian (EAS)

AF:

0.00104

AC:

AN:

13460

South Asian (SAS)

AF:

0.00239

AC:

AN:

7942

European-Finnish (FIN)

AF:

0.000620

AC:

AN:

8070

Middle Eastern (MID)

AF:

0.00186

AC:

AN:

538

European-Non Finnish (NFE)

AF:

0.000767

AC:

AN:

88682

Other (OTH)

AF:

0.00130

AC:

AN:

6932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00422

AC:

155

AN:

36758

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

AN XY:

16134

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

8168

American (AMR)

AF:

0.000645

AC:

AN:

3100

Ashkenazi Jewish (ASJ)

AF:

0.00368

AC:

AN:

1360

East Asian (EAS)

AF:

0.00

AC:

AN:

1452

South Asian (SAS)

AF:

0.00280

AC:

AN:

714

European-Finnish (FIN)

AF:

0.00258

AC:

AN:

388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00575

AC:

119

AN:

20688

Other (OTH)

AF:

0.00612

AC:

AN:

490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.24

Splicing

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