9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Position:

• chr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001256054.3(C9orf72):​c.-45+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC 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 0.029 (191 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C9orf72	NM_001256054.3	c.-45+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.-45+263_-45+264insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron_variant			NP_659442.2
C9orf72	NM_018325.5	c.-138_-137insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		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.-138_-137insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		upstream_gene_variant		1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 4079 AN: 141652 Hom.: 191 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.00236

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.0333

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0303

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 700 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 328

Gnomad4 SAS exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0288 AC: 4082 AN: 141730 Hom.: 191 Cov.: 0 AF XY: 0.0285 AC XY: 1964 AN XY: 68890

Gnomad4 AFR AF: 0.0389

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.0166

Gnomad4 SAS AF: 0.0150

Gnomad4 FIN AF: 0.0215

Gnomad4 NFE AF: 0.0273

Gnomad4 OTH AF: 0.0300

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;