rs10812615

Positions:

• chr9-27562235-T-C

Variant summary

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

The ENST00000380003.8(C9orf72):​c.600+146A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 365,862 control chromosomes in the GnomAD database, including 33,262 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 0.41 (13014 hom., cov: 33)
  • Exomes 𝑓: 0.43 (20248 hom.)
• Consequence: C9orf72 ENST00000380003.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320

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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.600+146A>G		intron_variant		ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.600+146A>G		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.600+146A>G		intron_variant			NP_659442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.600+146A>G		intron_variant		1	NM_018325.5	ENSP00000369339	P1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61821 AN: 151908 Hom.: 13000 Cov.: 33

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.388

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.430 AC: 91893 AN: 213836 Hom.: 20248 AF XY: 0.433 AC XY: 47663 AN XY: 109952

Gnomad4 AFR exome AF: 0.299

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.332

Gnomad4 SAS exome AF: 0.502

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.445

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.407 AC: 61868 AN: 152026 Hom.: 13014 Cov.: 33 AF XY: 0.408 AC XY: 30296 AN XY: 74296

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.418

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.454

Gnomad4 OTH AF: 0.397

Alfa AF: 0.441 Hom.: 4553

Bravo AF: 0.396

Asia WGS AF: 0.484 AC: 1682 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.9
DANN	Benign	0.84

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: rs10812615; hg19: chr9-27562233;