9-27573523-CGCCCCGGCCCCG-CGCCCCG

Position:

• chr9-27573523-CGCCCCGGCCCCG-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+185delCGGGGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 142,304 control chromosomes in the GnomAD database, including 20,541 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.53 (20425 hom., cov: 0)
  • Exomes 𝑓: 0.56 (116 hom.)
• Consequence: C9orf72 NM_001256054.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10

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 = 0.592 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+185delCGGGGC		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.-45+258_-45+263delCGGGGC		intron_variant			NP_659442.2
C9orf72	NM_018325.5	c.-143_-138delCGGGGC		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_-138delCGGGGC		upstream_gene_variant		1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.533 AC: 75404 AN: 141568 Hom.: 20418 Cov.: 0

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.493

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.545

GnomAD4 exome AF: 0.559 AC: 367 AN: 656 Hom.: 116 AF XY: 0.539 AC XY: 166 AN XY: 308

Gnomad4 SAS exome AF: 0.558

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.532 AC: 75427 AN: 141648 Hom.: 20425 Cov.: 0 AF XY: 0.537 AC XY: 36944 AN XY: 68850

Gnomad4 AFR AF: 0.441

Gnomad4 AMR AF: 0.547

Gnomad4 ASJ AF: 0.658

Gnomad4 EAS AF: 0.610

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.635

Gnomad4 NFE AF: 0.558

Gnomad4 OTH AF: 0.545

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;