9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCG

Position:

• chr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCG

Variant summary

Our verdict is Benign. Variant got -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. 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

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 (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C9orf72	NM_001256054.3	c.-45+174_-45+185dupCGGGGCCGGGGC		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.-45+252_-45+263dupCGGGGCCGGGGC		intron_variant			NP_659442.2
C9orf72	NM_018325.5	c.-149_-138dupCGGGGCCGGGGC		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.-149_-138dupCGGGGCCGGGGC		upstream_gene_variant		1	NM_018325.5	ENSP00000369339.3

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

Gnomad4 SAS exome AF: 0.103

Gnomad4 OTH exome AF: 0.250

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

Gnomad4 AFR AF: 0.0532

Gnomad4 AMR AF: 0.0989

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.00353

Gnomad4 SAS AF: 0.0781

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.118

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;