chr9-27573523-C-CGCCCCG

Variant names:

• chr9-27573523-C-CGCCCCG
• rs143561967
• ENST00000619707.5:c.-45+180_-45+185dupCGGGGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001256054.3(C9orf72):​c.-45+180_-45+185dupCGGGGC 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 0.033 (226 hom., cov: 0)
  • Exomes 𝑓: 0.064 (5 hom.)
• Consequence: C9orf72 NM_001256054.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• Publications: 4 publications found

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]

C9orf72 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• progressive myoclonus epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256054.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	NM_001256054.3		c.-45+180_-45+185dupCGGGGC		intron	N/A	NP_001242983.1	Q96LT7-1
	C9orf72	NM_145005.7		c.-45+258_-45+263dupCGGGGC		intron	N/A	NP_659442.2
	C9orf72	NM_018325.5	MANE Select	c.-143_-138dupCGGGGC		upstream_gene	N/A	NP_060795.1	Q96LT7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	ENST00000619707.5	TSL:1	c.-45+180_-45+185dupCGGGGC		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000965249.1		c.-45+180_-45+185dupCGGGGC		intron	N/A	ENSP00000635308.1
	C9orf72	ENST00000965246.1		c.-45+305_-45+310dupCGGGGC		intron	N/A	ENSP00000635305.1

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 4692 AN: 141646 Hom.: 224 Cov.: 0

Gnomad AFR AF: 0.0593

Gnomad AMI AF: 0.0402

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00744

Gnomad EAS AF: 0.00352

Gnomad SAS AF: 0.0874

Gnomad FIN AF: 0.00549

Gnomad MID AF: 0.0700

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0247

GnomAD4 exome AF: 0.0643 AC: 45 AN: 700 Hom.: 5 Cov.: 0 AF XY: 0.0518 AC XY: 17 AN XY: 328

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.0647 AC: 45 AN: 696

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0332 AC: 4702 AN: 141724 Hom.: 226 Cov.: 0 AF XY: 0.0330 AC XY: 2276 AN XY: 68888

African (AFR) AF: 0.0595 AC: 2318 AN: 38986

American (AMR) AF: 0.0188 AC: 273 AN: 14502

Ashkenazi Jewish (ASJ) AF: 0.00744 AC: 25 AN: 3358

East Asian (EAS) AF: 0.00353 AC: 17 AN: 4812

South Asian (SAS) AF: 0.0872 AC: 395 AN: 4530

European-Finnish (FIN) AF: 0.00549 AC: 45 AN: 8204

Middle Eastern (MID) AF: 0.0714 AC: 20 AN: 280

European-Non Finnish (NFE) AF: 0.0237 AC: 1525 AN: 64242

Other (OTH) AF: 0.0255 AC: 50 AN: 1964

Alfa AF: 0.0216 Hom.: 147

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.049
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143561967; hg19: chr9-27573521;