9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Variant names:

• chr9-27573523-C-CGCCCCGGCCCCGGCCCCGGCCCCG
• rs143561967
• ENST00000619707.5:c.-45+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGC

Variant summary

Our verdict is Benign. The variant received -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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• 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 (EAS) allele frequency at 95% confidence interval = 0.125 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+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	NP_001242983.1	Q96LT7-1
	C9orf72	NM_145005.7		c.-45+263_-45+264insCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	NP_659442.2
	C9orf72	NM_018325.5	MANE Select	c.-138_-137insCGGGGCCGGGGCCGGGGCCGGGGC		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+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000965249.1		c.-45+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000635308.1
	C9orf72	ENST00000965246.1		c.-45+310_-45+311insCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000635305.1

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

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: 0.0532 AC: 37 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: 0.0468 AC: 6637 AN: 141750 Hom.: 481 Cov.: 0 AF XY: 0.0479 AC XY: 3300 AN XY: 68894

African (AFR) AF: 0.0711 AC: 2772 AN: 38984

American (AMR) AF: 0.118 AC: 1711 AN: 14500

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 37 AN: 3358

East Asian (EAS) AF: 0.133 AC: 641 AN: 4812

South Asian (SAS) AF: 0.0406 AC: 184 AN: 4536

European-Finnish (FIN) AF: 0.00999 AC: 82 AN: 8208

Middle Eastern (MID) AF: 0.0107 AC: 3 AN: 280

European-Non Finnish (NFE) AF: 0.0176 AC: 1128 AN: 64262

Other (OTH) AF: 0.0382 AC: 75 AN: 1964

Alfa AF: 0.0227 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;