rs17769294

Positions:

chr9-27561630-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/19 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.86

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 366526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-27561630-T-C is described in Lovd as [Benign].

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/exons	MANE
C9orf72	NM_018325.5 linkuse as main transcript	c.620A>G	p.Asn207Ser	missense_variant	5/11	ENST00000380003.8
C9orf72	NM_001256054.3 linkuse as main transcript	c.620A>G	p.Asn207Ser	missense_variant	5/11
C9orf72	NM_145005.7 linkuse as main transcript	c.620A>G	p.Asn207Ser	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8 linkuse as main transcript	c.620A>G	p.Asn207Ser	missense_variant	5/11	1	NM_018325.5	P1	Q96LT7-1

Frequencies

GnomAD3 genomes

AF:

0.0953

AC:

14495

AN:

152022

Hom.:

874

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0995

AC:

24737

AN:

248546

Hom.:

1585

AF XY:

0.103

AC XY:

13900

AN XY:

134464

show subpopulations

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 SAS exome

AF:

0.0763

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.:

AF XY:

0.117

AC XY:

84720

AN XY:

722900

show subpopulations

Gnomad4 AFR exome

AF:

0.0271

Gnomad4 AMR exome

AF:

0.0500

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.000354

Gnomad4 SAS exome

AF:

0.0790

Gnomad4 FIN exome

AF:

0.172

Gnomad4 NFE exome

AF:

0.129

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.0953

AC:

14493

AN:

152140

Hom.:

874

Cov.:

AF XY:

0.0964

AC XY:

7173

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0341

Gnomad4 AMR

AF:

0.0792

Gnomad4 ASJ

AF:

0.0968

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0680

Gnomad4 FIN

AF:

0.185

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.0971

Alfa

AF:

0.119

Hom.:

2555

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

LINK: link

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 12, 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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

T;T;.;.;.;.

Eigen

Benign

-0.049

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;.;T;T;.;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.;.;L;L

MutationTaster

Benign

0.0000013

P;P;P

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

GERP RS

5.0

Varity_R

0.095

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over