rs2492816

Positions:

• chr9-27565107-G-A
• chr9-27565107-G-T

Variant summary

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

The NM_018325.5(C9orf72):​c.504+424C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 151,972 control chromosomes in the GnomAD database, including 13,273 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 (13273 hom., cov: 32)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.504+424C>T		intron_variant		ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.504+424C>T		intron_variant			NP_001242983.1
C9orf72	NM_145005.7	c.504+424C>T		intron_variant			NP_659442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.504+424C>T		intron_variant		1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62698 AN: 151854 Hom.: 13250 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.427

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

GnomAD4 genome AF: 0.413 AC: 62756 AN: 151972 Hom.: 13273 Cov.: 32 AF XY: 0.413 AC XY: 30675 AN XY: 74284

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.436

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.428

Alfa AF: 0.442 Hom.: 4089

Bravo AF: 0.412

Asia WGS AF: 0.448 AC: 1557 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.9
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2492816; hg19: chr9-27565105;