Genetic Variant C9orf72:c.1260-28_1260-14dupTTTTTTTTTTTTTTT (chr9-27548435-G-GAAAAAAAAAAAAAAA) – 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.1260-28_1260-14dupTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 0)

Exomes 𝑓: 0.000043 ( 0 hom. )

Failed GnomAD Quality Control

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BS2

High AC in GnomAd4 at 8 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.1260-28_1260-14dupTTTTTTTTTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-28_1260-14dupTTTTTTTTTTTTTTT		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.1260-28_1260-14dupTTTTTTTTTTTTTTT	intron	N/A	ENSP00000369339.3	Q96LT7-1
C9orf72	ENST00000619707.5	TSL:1	c.1260-28_1260-14dupTTTTTTTTTTTTTTT	intron	N/A	ENSP00000482753.1	Q96LT7-1
C9orf72	ENST00000644136.1		c.1293-28_1293-14dupTTTTTTTTTTTTTTT	intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes

AF:

0.000218

AC:

AN:

36772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000323

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00140

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000193

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000434

AC:

AN:

138130

Hom.:

Cov.:

AF XY:

0.0000560

AC XY:

AN XY:

71380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

3100

American (AMR)

AF:

0.000177

AC:

AN:

5658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3728

East Asian (EAS)

AF:

0.000223

AC:

AN:

13460

South Asian (SAS)

AF:

0.000126

AC:

AN:

7942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

538

European-Non Finnish (NFE)

AF:

0.0000113

AC:

AN:

88700

Other (OTH)

AF:

0.00

AC:

AN:

6934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.733

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000218

AC:

AN:

36764

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

AN XY:

16134

show subpopulations

African (AFR)

AF:

0.000245

AC:

AN:

8168

American (AMR)

AF:

0.000323

AC:

AN:

3100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1360

East Asian (EAS)

AF:

0.00

AC:

AN:

1452

South Asian (SAS)

AF:

0.00140

AC:

AN:

714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000193

AC:

AN:

20694

Other (OTH)

AF:

0.00

AC:

AN:

490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.783

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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9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

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