9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Position:

• chr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Variant summary

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

The NM_001256054.3(C9orf72):​c.-45+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGC 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 0.047 (481 hom., cov: 0)
  • Exomes 𝑓: 0.053 (7 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 = 0.125 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 6627 AN: 141672 Hom.: 481 Cov.: 0

Gnomad AFR AF: 0.0711

Gnomad AMI AF: 0.00473

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.0405

Gnomad FIN AF: 0.00999

Gnomad MID AF: 0.0100

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0386

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0529 AC: 37 AN: 700 Hom.: 7 Cov.: 0 AF XY: 0.0610 AC XY: 20 AN XY: 328

Gnomad4 SAS exome AF: 0.0532

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0468 AC: 6637 AN: 141750 Hom.: 481 Cov.: 0 AF XY: 0.0479 AC XY: 3300 AN XY: 68894

Gnomad4 AFR AF: 0.0711

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.0406

Gnomad4 FIN AF: 0.00999

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.0382

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;