9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCG

Variant names:

• chr9-27573523-C-CGCCCCGGCCCCG
• rs143561967
• ENST00000619707.5:c.-45+174_-45+185dupCGGGGCCGGGGC

Variant summary

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

The NM_001256054.3(C9orf72):​c.-45+174_-45+185dupCGGGGCCGGGGC 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 0.11 (1613 hom., cov: 0)
  • Exomes 𝑓: 0.10 (11 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 (NFE) allele frequency at 95% confidence interval = 0.152 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+174_-45+185dupCGGGGCCGGGGC		intron	N/A	NP_001242983.1	Q96LT7-1
	C9orf72	NM_145005.7		c.-45+252_-45+263dupCGGGGCCGGGGC		intron	N/A	NP_659442.2
	C9orf72	NM_018325.5	MANE Select	c.-149_-138dupCGGGGCCGGGGC		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+174_-45+185dupCGGGGCCGGGGC		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000965249.1		c.-45+174_-45+185dupCGGGGCCGGGGC		intron	N/A	ENSP00000635308.1
	C9orf72	ENST00000965246.1		c.-45+299_-45+310dupCGGGGCCGGGGC		intron	N/A	ENSP00000635305.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 16220 AN: 141630 Hom.: 1613 Cov.: 0

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.0990

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.00352

Gnomad SAS AF: 0.0777

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.110

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.119

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.104 AC: 73 AN: 700 Hom.: 11 Cov.: 0 AF XY: 0.116 AC XY: 38 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: 0.103 AC: 72 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: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.114 AC: 16221 AN: 141708 Hom.: 1613 Cov.: 0 AF XY: 0.115 AC XY: 7922 AN XY: 68868

African (AFR) AF: 0.0532 AC: 2074 AN: 38996

American (AMR) AF: 0.0989 AC: 1433 AN: 14496

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 347 AN: 3356

East Asian (EAS) AF: 0.00353 AC: 17 AN: 4812

South Asian (SAS) AF: 0.0781 AC: 354 AN: 4532

European-Finnish (FIN) AF: 0.196 AC: 1607 AN: 8188

Middle Eastern (MID) AF: 0.107 AC: 30 AN: 280

European-Non Finnish (NFE) AF: 0.155 AC: 9946 AN: 64240

Other (OTH) AF: 0.118 AC: 232 AN: 1964

Alfa AF: 0.144 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;