GeneBe

rs143561967

Variant names:

Variant summary

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

The NM_001256054.3(C9orf72):​c.-45+174_-45+185delCGGGGCCGGGGC 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 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: 𝑓 0.000042 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

C9orf72
NM_001256054.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.10

Publications

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

BS2
High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256054.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
C9orf72
NM_001256054.3
c.-45+174_-45+185delCGGGGCCGGGGC
intron
N/ANP_001242983.1Q96LT7-1
C9orf72
NM_145005.7
c.-45+252_-45+263delCGGGGCCGGGGC
intron
N/ANP_659442.2
C9orf72
NM_018325.5
MANE Select
c.-149_-138delCGGGGCCGGGGC
upstream_gene
N/ANP_060795.1Q96LT7-1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
C9orf72
ENST00000619707.5
TSL:1
c.-45+174_-45+185delCGGGGCCGGGGC
intron
N/AENSP00000482753.1Q96LT7-1
C9orf72
ENST00000965249.1
c.-45+174_-45+185delCGGGGCCGGGGC
intron
N/AENSP00000635308.1
C9orf72
ENST00000965246.1
c.-45+299_-45+310delCGGGGCCGGGGC
intron
N/AENSP00000635305.1

Frequencies

GnomAD3 genomes
AF:
0.0000423
AC:
6
AN:
141698
Hom.:
0
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.000154
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
700
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
328
African (AFR)
AC:
0
AN:
0
American (AMR)
AC:
0
AN:
0
Ashkenazi Jewish (ASJ)
AC:
0
AN:
0
East Asian (EAS)
AC:
0
AN:
0
South Asian (SAS)
AF:
0.00
AC:
0
AN:
696
European-Finnish (FIN)
AC:
0
AN:
0
Middle Eastern (MID)
AC:
0
AN:
0
European-Non Finnish (NFE)
AC:
0
AN:
0
Other (OTH)
AF:
0.00
AC:
0
AN:
4
GnomAD4 genome
AF:
0.0000423
AC:
6
AN:
141698
Hom.:
0
Cov.:
0
AF XY:
0.0000291
AC XY:
2
AN XY:
68822
show subpopulations
African (AFR)
AF:
0.000154
AC:
6
AN:
38902
American (AMR)
AF:
0.00
AC:
0
AN:
14490
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3358
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4826
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4550
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8208
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
300
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
64274
Other (OTH)
AF:
0.00
AC:
0
AN:
1944
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.558
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.00
Hom.:
147

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.1

Splicing

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

Publications

Other links and lift over

dbSNP: rs143561967; hg19: chr9-27573521; API