9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Position:

• chr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Variant summary

Our verdict is Benign. Variant got -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. 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

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C9orf72	NM_001256054.3	c.-45+168_-45+185dupCGGGGCCGGGGCCGGGGC		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.-45+246_-45+263dupCGGGGCCGGGGCCGGGGC		intron_variant			NP_659442.2
C9orf72	NM_018325.5	c.-155_-138dupCGGGGCCGGGGCCGGGGC		upstream_gene_variant		ENST00000380003.8	NP_060795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.-155_-138dupCGGGGCCGGGGCCGGGGC		upstream_gene_variant		1	NM_018325.5	ENSP00000369339.3

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

Gnomad4 SAS exome AF: 0.102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0622 AC: 8819 AN: 141736 Hom.: 581 Cov.: 0 AF XY: 0.0604 AC XY: 4161 AN XY: 68884

Gnomad4 AFR AF: 0.0828

Gnomad4 AMR AF: 0.0520

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.0858

Gnomad4 FIN AF: 0.0262

Gnomad4 NFE AF: 0.0545

Gnomad4 OTH AF: 0.0616

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143561967; hg19: chr9-27573521;