rs12686452

Positions:

• chr9-27555018-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018325.5(C9orf72):​c.1091+1543A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 151,998 control chromosomes in the GnomAD database, including 4,061 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4061 hom., cov: 32)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9orf72	NM_018325.5	c.1091+1543A>G		intron_variant		ENST00000380003.8
C9orf72	NM_001256054.3	c.1091+1543A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8	c.1091+1543A>G		intron_variant		1	NM_018325.5	P1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33386 AN: 151880 Hom.: 4053 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.216

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.220 AC: 33404 AN: 151998 Hom.: 4061 Cov.: 32 AF XY: 0.224 AC XY: 16614 AN XY: 74280

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.218

Alfa AF: 0.239 Hom.: 1869

Bravo AF: 0.216

Asia WGS AF: 0.285 AC: 992 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.9
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs12686452; hg19: chr9-27555016;