rs10812616

Positions:

• chr9-27562295-T-A
• chr9-27562295-T-C
• chr9-27562295-T-G

Variant summary

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

The NM_018325.5(C9orf72):​c.600+86A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 490,826 control chromosomes in the GnomAD database, including 46,461 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 (12967 hom., cov: 32)
  • Exomes 𝑓: 0.44 (33494 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320

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=-0.86).
• 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+86A>T		intron_variant		ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.600+86A>T		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.600+86A>T		intron_variant			NP_659442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.600+86A>T		intron_variant		1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61650 AN: 151770 Hom.: 12952 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.441 AC: 149387 AN: 338938 Hom.: 33494 AF XY: 0.443 AC XY: 77623 AN XY: 175384

Gnomad4 AFR exome AF: 0.299

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.404

Gnomad4 EAS exome AF: 0.336

Gnomad4 SAS exome AF: 0.486

Gnomad4 FIN exome AF: 0.482

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.417

GnomAD4 genome AF: 0.406 AC: 61698 AN: 151888 Hom.: 12967 Cov.: 32 AF XY: 0.407 AC XY: 30240 AN XY: 74256

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.417

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.484

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.398

Alfa AF: 0.430 Hom.: 1745

Bravo AF: 0.395

Asia WGS AF: 0.485 AC: 1674 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.6
DANN	Benign	0.36

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: rs10812616; hg19: chr9-27562293;