chr9-27573523-C-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 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 0.013 (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
• 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.

• 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1814 AD gene.

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+186insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	NP_001242983.1	Q96LT7-1
	C9orf72	NM_145005.7		c.-45+263_-45+264insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	NP_659442.2
	C9orf72	NM_018325.5	MANE Select	c.-138_-137insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		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+186insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000965249.1		c.-45+185_-45+186insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000635308.1
	C9orf72	ENST00000965246.1		c.-45+310_-45+311insCGGGGCCGGGGCCGGGGCCGGGGCCGGGGCCGGGGC		intron	N/A	ENSP00000635305.1

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

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

African (AFR) AF: 0.0252 AC: 982 AN: 38996

American (AMR) AF: 0.0159 AC: 230 AN: 14504

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 47 AN: 3358

East Asian (EAS) AF: 0.00769 AC: 37 AN: 4812

South Asian (SAS) AF: 0.0183 AC: 83 AN: 4538

European-Finnish (FIN) AF: 0.000853 AC: 7 AN: 8208

Middle Eastern (MID) AF: 0.0214 AC: 6 AN: 280

European-Non Finnish (NFE) AF: 0.00608 AC: 391 AN: 64262

Other (OTH) AF: 0.00916 AC: 18 AN: 1964

Alfa AF: 0.00 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;