chr9-27561630-T-C
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1
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
NM_018325.5 missense
Scores
2
12
Clinical Significance
Conservation
PhyloP100: 1.86
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 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_single_submitter, 1 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 | UniProt |
---|---|---|---|---|---|---|---|
C9orf72 | NM_018325.5 | c.620A>G | p.Asn207Ser | missense_variant | 5/11 | ENST00000380003.8 | |
C9orf72 | NM_001256054.3 | c.620A>G | p.Asn207Ser | missense_variant | 5/11 | ||
C9orf72 | NM_145005.7 | c.620A>G | p.Asn207Ser | missense_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
C9orf72 | ENST00000380003.8 | c.620A>G | p.Asn207Ser | missense_variant | 5/11 | 1 | NM_018325.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0953 AC: 14495AN: 152022Hom.: 874 Cov.: 32
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GnomAD3 exomes AF: 0.0995 AC: 24737AN: 248546Hom.: 1585 AF XY: 0.103 AC XY: 13900AN XY: 134464
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GnomAD4 exome AF: 0.117 AC: 170549AN: 1452262Hom.: 11056 Cov.: 29 AF XY: 0.117 AC XY: 84720AN XY: 722900
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GnomAD4 genome ? AF: 0.0953 AC: 14493AN: 152140Hom.: 874 Cov.: 32 AF XY: 0.0964 AC XY: 7173AN XY: 74390
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, single submitter
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 | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T;.;T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.;L;L
MutationTaster
Benign
P;P;P
Sift4G
Benign
T;T;.;.;D;D
Polyphen
B;B;.;.;B;B
Vest4
MPC
0.099
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at