rs12349820

chr9-27553878-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+2683A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 151,902 control chromosomes in the GnomAD database, including 3,098 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 0.19 (3098 hom., cov: 32)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308

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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9orf72	NM_018325.5	c.1091+2683A>G		intron_variant		ENST00000380003.8
C9orf72	NM_001256054.3	c.1091+2683A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8	c.1091+2683A>G		intron_variant		1	NM_018325.5	P1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29507 AN: 151786 Hom.: 3096 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.180

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

GnomAD4 genome AF: 0.194 AC: 29512 AN: 151902 Hom.: 3098 Cov.: 32 AF XY: 0.193 AC XY: 14294 AN XY: 74230

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.183

Alfa AF: 0.224 Hom.: 7166

Bravo AF: 0.182

Asia WGS AF: 0.178 AC: 616 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	4.6
Dann	Benign	0.78

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: rs12349820; hg19: chr9-27553876; COSMIC: COSV66163932; COSMIC: COSV66163932;