rs10122902

chr9-27556782-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_018325.5(C9orf72):c.870C>T(p.Ser290=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,609,536 control chromosomes in the GnomAD database, including 36,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3437 hom., cov: 33)
  • Exomes 𝑓: 0.21 (32681 hom.)
• Consequence: C9orf72 NM_018325.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.04

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 9-27556782-G-A is Benign according to our data. Variant chr9-27556782-G-A is described in ClinVar as [Benign]. Clinvar id is 366524.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-27556782-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9orf72	NM_018325.5	c.870C>T	p.Ser290=	synonymous_variant	8/11	ENST00000380003.8
C9orf72	NM_001256054.3	c.870C>T	p.Ser290=	synonymous_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8	c.870C>T	p.Ser290=	synonymous_variant	8/11	1	NM_018325.5	P1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31790 AN: 151996 Hom.: 3423 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.237 AC: 59130 AN: 249814 Hom.: 7457 AF XY: 0.234 AC XY: 31576 AN XY: 135032

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.314

Gnomad SAS exome AF: 0.259

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.207 AC: 302344 AN: 1457422 Hom.: 32681 Cov.: 30 AF XY: 0.209 AC XY: 151382 AN XY: 725254

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.209 AC: 31824 AN: 152114 Hom.: 3437 Cov.: 33 AF XY: 0.212 AC XY: 15738 AN XY: 74366

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.303

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.210

Alfa AF: 0.204 Hom.: 7728

Bravo AF: 0.214

Asia WGS AF: 0.286 AC: 997 AN: 3478

EpiCase AF: 0.191

EpiControl AF: 0.195

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	8.2
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs10122902; hg19: chr9-27556780; COSMIC: COSV66155178; COSMIC: COSV66155178;