9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Variant names:

• chr9-27573523-C-CGCCCCGGCCCCGGCCCCG
• rs143561967
• ENST00000619707.5:c.-45+168_-45+185dupCGGGGCCGGGGCCGGGGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001256054.3(C9orf72):​c.-45+168_-45+185dupCGGGGCCGGGGCCGGGGC 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 0.062 (581 hom., cov: 0)
  • Exomes 𝑓: 0.10 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: C9orf72 NM_001256054.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

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.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	NM_001256054.3		c.-45+168_-45+185dupCGGGGCCGGGGCCGGGGC		intron	N/A	NP_001242983.1	Q96LT7-1
	C9orf72	NM_145005.7		c.-45+246_-45+263dupCGGGGCCGGGGCCGGGGC		intron	N/A	NP_659442.2
	C9orf72	NM_018325.5	MANE Select	c.-155_-138dupCGGGGCCGGGGCCGGGGC		upstream_gene	N/A	NP_060795.1	Q96LT7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	ENST00000619707.5	TSL:1	c.-45+168_-45+185dupCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000965249.1		c.-45+168_-45+185dupCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000635308.1
	C9orf72	ENST00000965246.1		c.-45+293_-45+310dupCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000635305.1

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 8811 AN: 141658 Hom.: 578 Cov.: 0

Gnomad AFR AF: 0.0828

Gnomad AMI AF: 0.0201

Gnomad AMR AF: 0.0521

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0864

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.0433

Gnomad NFE AF: 0.0545

Gnomad OTH AF: 0.0576

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.101 AC: 71 AN: 700 Hom.: 13 Cov.: 0 AF XY: 0.0976 AC XY: 32 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: 0.102 AC: 71 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: 0.0622 AC: 8819 AN: 141736 Hom.: 581 Cov.: 0 AF XY: 0.0604 AC XY: 4161 AN XY: 68884

African (AFR) AF: 0.0828 AC: 3227 AN: 38994

American (AMR) AF: 0.0520 AC: 754 AN: 14498

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 61 AN: 3358

East Asian (EAS) AF: 0.108 AC: 520 AN: 4810

South Asian (SAS) AF: 0.0858 AC: 389 AN: 4534

European-Finnish (FIN) AF: 0.0262 AC: 215 AN: 8202

Middle Eastern (MID) AF: 0.0464 AC: 13 AN: 280

European-Non Finnish (NFE) AF: 0.0545 AC: 3502 AN: 64252

Other (OTH) AF: 0.0616 AC: 121 AN: 1964

Alfa AF: 0.0570 Hom.: 147

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.049
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs143561967; hg19: chr9-27573521;