9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGTCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Position:

• chr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGTCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Variant summary

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

The NM_001256054.3(C9orf72):​c.-45+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGACCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC 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 0.0000071 (0 hom., cov: 0)
• 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+186insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGACCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.-45+263_-45+264insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGACCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron_variant			NP_659442.2
C9orf72	NM_018325.5	c.-138_-137insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGACCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		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_-137insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGACCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		upstream_gene_variant		1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.00000706 AC: 1 AN: 141698 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000690

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00000706 AC: 1 AN: 141698 Hom.: 0 Cov.: 0 AF XY: 0.0000145 AC XY: 1 AN XY: 68822

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000690

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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;