GeneBe

rs11292923

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018325.5(C9orf72):​c.1260-31_1260-14delTTTTTTTTTTTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.00000724 in 138,130 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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: not found (cov: 0)
Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.15

Publications

0 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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
C9orf72
NM_018325.5
MANE Select
c.1260-31_1260-14delTTTTTTTTTTTTTTTTTT
intron
N/ANP_060795.1Q96LT7-1
C9orf72
NM_001256054.3
c.1260-31_1260-14delTTTTTTTTTTTTTTTTTT
intron
N/ANP_001242983.1Q96LT7-1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
C9orf72
ENST00000380003.8
TSL:1 MANE Select
c.1260-31_1260-14delTTTTTTTTTTTTTTTTTT
intron
N/AENSP00000369339.3Q96LT7-1
C9orf72
ENST00000619707.5
TSL:1
c.1260-31_1260-14delTTTTTTTTTTTTTTTTTT
intron
N/AENSP00000482753.1Q96LT7-1
C9orf72
ENST00000644136.1
c.1293-31_1293-14delTTTTTTTTTTTTTTTTTT
intron
N/AENSP00000494872.1A0A2R8Y5K2

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD4 exome
AF:
0.00000724
AC:
1
AN:
138130
Hom.:
0
AF XY:
0.0000140
AC XY:
1
AN XY:
71380
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
3100
American (AMR)
AF:
0.00
AC:
0
AN:
5658
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3728
East Asian (EAS)
AF:
0.00
AC:
0
AN:
13460
South Asian (SAS)
AF:
0.00
AC:
0
AN:
7942
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8070
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
538
European-Non Finnish (NFE)
AF:
0.0000113
AC:
1
AN:
88700
Other (OTH)
AF:
0.00
AC:
0
AN:
6934
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
0

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

Other links and lift over

dbSNP: rs11292923; hg19: chr9-27548433; API