rs1565948

Variant names:

• chr9-27559735-G-A
• rs1565948
• NM_018325.5:c.738+492C>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.738+492C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 151,906 control chromosomes in the GnomAD database, including 15,096 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 0.44 (15093 hom., cov: 32)
  • Exomes 𝑓: 0.56 (3 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235
• Publications: 13 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 -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 = 0.492 is higher than 0.05.

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.738+492C>T		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.738+492C>T		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.738+492C>T		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.738+492C>T		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.738+492C>T		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66175 AN: 151770 Hom.: 15080 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.391

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.418

GnomAD4 exome AF: 0.556 AC: 10 AN: 18 Hom.: 3 Cov.: 0 AF XY: 0.875 AC XY: 7 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.556 AC: 10 AN: 18

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.436 AC: 66216 AN: 151888 Hom.: 15093 Cov.: 32 AF XY: 0.437 AC XY: 32428 AN XY: 74244

African (AFR) AF: 0.303 AC: 12550 AN: 41426

American (AMR) AF: 0.439 AC: 6692 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3466

East Asian (EAS) AF: 0.419 AC: 2167 AN: 5174

South Asian (SAS) AF: 0.501 AC: 2412 AN: 4814

European-Finnish (FIN) AF: 0.555 AC: 5850 AN: 10544

Middle Eastern (MID) AF: 0.383 AC: 111 AN: 290

European-Non Finnish (NFE) AF: 0.497 AC: 33736 AN: 67906

Other (OTH) AF: 0.424 AC: 895 AN: 2112

Alfa AF: 0.480 Hom.: 30203

Bravo AF: 0.420

Asia WGS AF: 0.489 AC: 1690 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.65
PhyloP100		0.23
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: rs1565948; hg19: chr9-27559733;