Genetic Variant C9orf72:c.1260-22_1260-14delTTTTTTTTT (chr9-27548435-GAAAAAAAAA-G) – 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.1260-22_1260-14delTTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.00106 in 174,868 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0012 ( 0 hom. )

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.15

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 26 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.1260-22_1260-14delTTTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-22_1260-14delTTTTTTTTT		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.1260-22_1260-14delTTTTTTTTT	intron	N/A	ENSP00000369339.3	Q96LT7-1
C9orf72	ENST00000619707.5	TSL:1	c.1260-22_1260-14delTTTTTTTTT	intron	N/A	ENSP00000482753.1	Q96LT7-1
C9orf72	ENST00000644136.1		c.1293-22_1293-14delTTTTTTTTT	intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes

AF:

0.000707

AC:

AN:

36772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000858

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00323

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00137

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00115

AC:

159

AN:

138096

Hom.:

AF XY:

0.00129

AC XY:

AN XY:

71360

show subpopulations

African (AFR)

AF:

0.00291

AC:

AN:

3098

American (AMR)

AF:

0.00230

AC:

AN:

5652

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

3728

East Asian (EAS)

AF:

0.000595

AC:

AN:

13454

South Asian (SAS)

AF:

0.000252

AC:

AN:

7940

European-Finnish (FIN)

AF:

0.000124

AC:

AN:

8066

Middle Eastern (MID)

AF:

0.00186

AC:

AN:

538

European-Non Finnish (NFE)

AF:

0.00127

AC:

113

AN:

88690

Other (OTH)

AF:

0.00159

AC:

AN:

6930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000707

AC:

AN:

36772

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

16126

show subpopulations

African (AFR)

AF:

0.000858

AC:

AN:

8160

American (AMR)

AF:

0.00323

AC:

AN:

3094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1360

East Asian (EAS)

AF:

0.00137

AC:

AN:

1458

South Asian (SAS)

AF:

0.00

AC:

AN:

716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

20700

Other (OTH)

AF:

0.00

AC:

AN:

490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAA

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