9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Position:

• chr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001256054.3(C9orf72):​c.-45+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC 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 0.013 (81 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 Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1814/141768) while in subpopulation AFR AF= 0.0252 (982/38996). AF 95% confidence interval is 0.0239. There are 81 homozygotes in gnomad4. There are 873 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1814 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1815 AN: 141690 Hom.: 81 Cov.: 0

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0140

Gnomad EAS AF: 0.00767

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.000853

Gnomad MID AF: 0.0233

Gnomad NFE AF: 0.00608

Gnomad OTH AF: 0.00926

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 AF: 0.0128 AC: 1814 AN: 141768 Hom.: 81 Cov.: 0 AF XY: 0.0127 AC XY: 873 AN XY: 68912

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0140

Gnomad4 EAS AF: 0.00769

Gnomad4 SAS AF: 0.0183

Gnomad4 FIN AF: 0.000853

Gnomad4 NFE AF: 0.00608

Gnomad4 OTH AF: 0.00916

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;