9-27573523-C-CGCCCCG

Position:

• chr9-27573523-C-CGCCCCG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001256054.3(C9orf72):​c.-45+180_-45+185dupCGGGGC 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 0.033 (226 hom., cov: 0)
  • Exomes 𝑓: 0.064 (5 hom.)
• 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 (SAS) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C9orf72	NM_001256054.3	c.-45+180_-45+185dupCGGGGC		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.-45+258_-45+263dupCGGGGC		intron_variant			NP_659442.2
C9orf72	NM_018325.5	c.-143_-138dupCGGGGC		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.-143_-138dupCGGGGC		upstream_gene_variant		1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 4692 AN: 141646 Hom.: 224 Cov.: 0

Gnomad AFR AF: 0.0593

Gnomad AMI AF: 0.0402

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00744

Gnomad EAS AF: 0.00352

Gnomad SAS AF: 0.0874

Gnomad FIN AF: 0.00549

Gnomad MID AF: 0.0700

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0247

GnomAD4 exome AF: 0.0643 AC: 45 AN: 700 Hom.: 5 Cov.: 0 AF XY: 0.0518 AC XY: 17 AN XY: 328

Gnomad4 SAS exome AF: 0.0647

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0332 AC: 4702 AN: 141724 Hom.: 226 Cov.: 0 AF XY: 0.0330 AC XY: 2276 AN XY: 68888

Gnomad4 AFR AF: 0.0595

Gnomad4 AMR AF: 0.0188

Gnomad4 ASJ AF: 0.00744

Gnomad4 EAS AF: 0.00353

Gnomad4 SAS AF: 0.0872

Gnomad4 FIN AF: 0.00549

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0255

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;