rs10812616

Variant names:

• chr9-27562295-T-A
• rs10812616
• NM_018325.5:c.600+86A>T

Your query was ambiguous. Multiple possible variants found:

• chr9-27562295-T-A
• chr9-27562295-T-C
• chr9-27562295-T-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+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
• Publications: 5 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=-0.86).
• 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 rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.600+86A>T		intron_variant	Intron 4 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.600+86A>T		intron_variant	Intron 4 of 10		NP_001242983.1
C9orf72	NM_145005.7	c.600+86A>T		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+86A>T		intron_variant	Intron 4 of 10	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

African (AFR) AF: 0.299 AC: 2439 AN: 8160

American (AMR) AF: 0.420 AC: 3282 AN: 7822

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 3906 AN: 9658

East Asian (EAS) AF: 0.336 AC: 7547 AN: 22434

South Asian (SAS) AF: 0.486 AC: 3878 AN: 7976

European-Finnish (FIN) AF: 0.482 AC: 13962 AN: 28946

Middle Eastern (MID) AF: 0.365 AC: 531 AN: 1454

European-Non Finnish (NFE) AF: 0.454 AC: 106019 AN: 233748

Other (OTH) AF: 0.417 AC: 7823 AN: 18740

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

African (AFR) AF: 0.296 AC: 12256 AN: 41468

American (AMR) AF: 0.417 AC: 6368 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1386 AN: 3468

East Asian (EAS) AF: 0.417 AC: 2155 AN: 5166

South Asian (SAS) AF: 0.489 AC: 2364 AN: 4830

European-Finnish (FIN) AF: 0.484 AC: 5060 AN: 10464

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.453 AC: 30801 AN: 67924

Other (OTH) AF: 0.398 AC: 838 AN: 2106

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
PhyloP100		0.032
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: rs10812616; hg19: chr9-27562293;