chr9-27548435-GAAAAAAAAAAA-G

Variant names:

• chr9-27548435-GAAAAAAAAAAA-G
• rs11292923
• NM_018325.5:c.1260-24_1260-14delTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_018325.5(C9orf72):​c.1260-24_1260-14delTTTTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.00671 in 174,890 control chromosomes in the GnomAD database, including 12 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0083 (5 hom., cov: 0)
  • Exomes 𝑓: 0.0063 (7 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.15
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• progressive myoclonus epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00832 (306/36778) while in subpopulation AFR AF = 0.0306 (250/8180). AF 95% confidence interval is 0.0275. There are 5 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 306 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	NM_018325.5	MANE Select	c.1260-24_1260-14delTTTTTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-24_1260-14delTTTTTTTTTTT		intron	N/A	NP_001242983.1	Q96LT7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.1260-24_1260-14delTTTTTTTTTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-24_1260-14delTTTTTTTTTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-24_1293-14delTTTTTTTTTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 306 AN: 36786 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00226

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00140

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00227

Gnomad OTH AF: 0.00204

GnomAD4 exome AF: 0.00628 AC: 868 AN: 138112 Hom.: 7 AF XY: 0.00539 AC XY: 385 AN XY: 71370

African (AFR) AF: 0.0546 AC: 169 AN: 3098

American (AMR) AF: 0.000530 AC: 3 AN: 5656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3728

East Asian (EAS) AF: 0.0000743 AC: 1 AN: 13458

South Asian (SAS) AF: 0.000881 AC: 7 AN: 7942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8070

Middle Eastern (MID) AF: 0.00743 AC: 4 AN: 538

European-Non Finnish (NFE) AF: 0.00705 AC: 625 AN: 88690

Other (OTH) AF: 0.00851 AC: 59 AN: 6932

GnomAD4 genome AF: 0.00832 AC: 306 AN: 36778 Hom.: 5 Cov.: 0 AF XY: 0.00886 AC XY: 143 AN XY: 16142

African (AFR) AF: 0.0306 AC: 250 AN: 8180

American (AMR) AF: 0.00226 AC: 7 AN: 3100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1360

East Asian (EAS) AF: 0.00 AC: 0 AN: 1452

South Asian (SAS) AF: 0.00140 AC: 1 AN: 714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.00227 AC: 47 AN: 20696

Other (OTH) AF: 0.00204 AC: 1 AN: 490

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11292923; hg19: chr9-27548433;