chr9-27561630-T-C

Variant names:

• chr9-27561630-T-C
• rs17769294
• NM_018325.5:c.620A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018325.5(C9orf72):​c.620A>G​(p.Asn207Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,604,402 control chromosomes in the GnomAD database, including 11,930 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (874 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11056 hom.)
• Consequence: C9orf72 NM_018325.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.86
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015868247).
• BP6: Variant 9-27561630-T-C is Benign according to our data. Variant chr9-27561630-T-C is described in ClinVar as Benign. ClinVar VariationId is 366526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.620A>G	p.Asn207Ser	missense_variant	Exon 5 of 11	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.620A>G	p.Asn207Ser	missense_variant	Exon 5 of 11		NP_001242983.1
C9orf72	NM_145005.7	c.620A>G	p.Asn207Ser	missense_variant	Exon 5 of 5		NP_659442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.620A>G	p.Asn207Ser	missense_variant	Exon 5 of 11	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.0953 AC: 14495 AN: 152022 Hom.: 874 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0794

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0681

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.0981

GnomAD2 exomes AF: 0.0995 AC: 24737 AN: 248546 AF XY: 0.103

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.0449

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.117 AC: 170549 AN: 1452262 Hom.: 11056 Cov.: 29 AF XY: 0.117 AC XY: 84720 AN XY: 722900

African (AFR) AF: 0.0271 AC: 900 AN: 33220

American (AMR) AF: 0.0500 AC: 2215 AN: 44280

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2614 AN: 26008

East Asian (EAS) AF: 0.000354 AC: 14 AN: 39516

South Asian (SAS) AF: 0.0790 AC: 6773 AN: 85698

European-Finnish (FIN) AF: 0.172 AC: 9195 AN: 53348

Middle Eastern (MID) AF: 0.0875 AC: 502 AN: 5740

European-Non Finnish (NFE) AF: 0.129 AC: 142254 AN: 1104436

Other (OTH) AF: 0.101 AC: 6082 AN: 60016

GnomAD4 genome AF: 0.0953 AC: 14493 AN: 152140 Hom.: 874 Cov.: 32 AF XY: 0.0964 AC XY: 7173 AN XY: 74390

African (AFR) AF: 0.0341 AC: 1416 AN: 41548

American (AMR) AF: 0.0792 AC: 1210 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 335 AN: 3460

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0680 AC: 328 AN: 4826

European-Finnish (FIN) AF: 0.185 AC: 1956 AN: 10594

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8837 AN: 67944

Other (OTH) AF: 0.0971 AC: 205 AN: 2112

Alfa AF: 0.113 Hom.: 3263

Bravo AF: 0.0863

TwinsUK AF: 0.128 AC: 474

ALSPAC AF: 0.126 AC: 484

ESP6500AA AF: 0.0340 AC: 150

ESP6500EA AF: 0.126 AC: 1085

ExAC AF: 0.102 AC: 12437

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.128

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T;.;.;.;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;.;T;T;.;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.;.;L;L
PhyloP100		1.9
PROVEAN	Benign	-0.33	.;N;.;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.48	.;T;.;.;T;T
Sift4G	Benign	0.19	T;T;.;.;D;D
Polyphen		0.0	B;B;.;.;B;B
Vest4		0.21
MPC		0.099
ClinPred		0.0081	T
GERP RS		5.0
Varity_R		0.095
gMVP		0.40
Mutation Taster		=96/4	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: rs17769294; hg19: chr9-27561628; COSMIC: COSV108915535;