rs2492816

Variant names:

• chr9-27565107-G-A
• rs2492816
• NM_018325.5:c.504+424C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive myoclonus epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.504+424C>T		intron_variant	Intron 3 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.504+424C>T		intron_variant	Intron 3 of 10		NP_001242983.1
C9orf72	NM_145005.7	c.504+424C>T		intron_variant	Intron 3 of 4		NP_659442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.504+424C>T		intron_variant	Intron 3 of 10	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

African (AFR) AF: 0.334 AC: 13851 AN: 41444

American (AMR) AF: 0.436 AC: 6649 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1211 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2055 AN: 5160

South Asian (SAS) AF: 0.469 AC: 2257 AN: 4816

European-Finnish (FIN) AF: 0.406 AC: 4288 AN: 10566

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30911 AN: 67944

Other (OTH) AF: 0.428 AC: 902 AN: 2108

Alfa AF: 0.440 Hom.: 4123

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
PhyloP100		0.034
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2492816; hg19: chr9-27565105;