chr9-27573523-CGCCCCG-C

Variant names:

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

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+185delCGGGGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 142,304 control chromosomes in the GnomAD database, including 20,541 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.53 (20425 hom., cov: 0)
  • Exomes 𝑓: 0.56 (116 hom.)
• Consequence: C9orf72 NM_001256054.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• 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 = 0.592 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+185delCGGGGC		intron	N/A	NP_001242983.1	Q96LT7-1
	C9orf72	NM_145005.7		c.-45+258_-45+263delCGGGGC		intron	N/A	NP_659442.2
	C9orf72	NM_018325.5	MANE Select	c.-143_-138delCGGGGC		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+185delCGGGGC		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000965249.1		c.-45+180_-45+185delCGGGGC		intron	N/A	ENSP00000635308.1
	C9orf72	ENST00000965246.1		c.-45+305_-45+310delCGGGGC		intron	N/A	ENSP00000635305.1

Frequencies

GnomAD3 genomes AF: 0.533 AC: 75404 AN: 141568 Hom.: 20418 Cov.: 0

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.493

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.545

GnomAD4 exome AF: 0.559 AC: 367 AN: 656 Hom.: 116 AF XY: 0.539 AC XY: 166 AN XY: 308

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: 0.558 AC: 364 AN: 652

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: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.532 AC: 75427 AN: 141648 Hom.: 20425 Cov.: 0 AF XY: 0.537 AC XY: 36944 AN XY: 68850

African (AFR) AF: 0.441 AC: 17187 AN: 38948

American (AMR) AF: 0.547 AC: 7929 AN: 14490

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2210 AN: 3360

East Asian (EAS) AF: 0.610 AC: 2935 AN: 4810

South Asian (SAS) AF: 0.556 AC: 2519 AN: 4532

European-Finnish (FIN) AF: 0.635 AC: 5208 AN: 8198

Middle Eastern (MID) AF: 0.482 AC: 135 AN: 280

European-Non Finnish (NFE) AF: 0.558 AC: 35808 AN: 64220

Other (OTH) AF: 0.545 AC: 1071 AN: 1966

Alfa AF: 0.583 Hom.: 147

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
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;