rs10812615

Variant names:

• chr9-27562235-T-C
• rs10812615
• NM_018325.5:c.600+146A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018325.5(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 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• Publications: 4 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=-0.82).
• 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 rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.600+146A>G		intron_variant	Intron 4 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.600+146A>G		intron_variant	Intron 4 of 10		NP_001242983.1
C9orf72	NM_145005.7	c.600+146A>G		intron_variant	Intron 4 of 4		NP_659442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.600+146A>G		intron_variant	Intron 4 of 10	1	NM_018325.5	ENSP00000369339.3

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

African (AFR) AF: 0.299 AC: 1878 AN: 6286

American (AMR) AF: 0.420 AC: 2769 AN: 6588

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 3203 AN: 7818

East Asian (EAS) AF: 0.332 AC: 6417 AN: 19318

South Asian (SAS) AF: 0.502 AC: 1201 AN: 2392

European-Finnish (FIN) AF: 0.481 AC: 8283 AN: 17224

Middle Eastern (MID) AF: 0.369 AC: 419 AN: 1134

European-Non Finnish (NFE) AF: 0.445 AC: 62008 AN: 139192

Other (OTH) AF: 0.412 AC: 5715 AN: 13884

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

African (AFR) AF: 0.297 AC: 12338 AN: 41474

American (AMR) AF: 0.418 AC: 6389 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1387 AN: 3466

East Asian (EAS) AF: 0.418 AC: 2161 AN: 5176

South Asian (SAS) AF: 0.489 AC: 2365 AN: 4832

European-Finnish (FIN) AF: 0.483 AC: 5082 AN: 10526

Middle Eastern (MID) AF: 0.379 AC: 110 AN: 290

European-Non Finnish (NFE) AF: 0.454 AC: 30836 AN: 67958

Other (OTH) AF: 0.397 AC: 839 AN: 2114

Alfa AF: 0.439 Hom.: 4593

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
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10812615; hg19: chr9-27562233;