9-35059793-T-C
Variant summary
Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_007126.5(VCP):c.1704A>G(p.Gln568Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,614,084 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_007126.5 synonymous
Scores
Clinical Significance
Conservation
Publications
- complex neurodevelopmental disorderInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- inclusion body myopathy with Paget disease of bone and frontotemporal dementiaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Charcot-Marie-Tooth disease type 2YInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- frontotemporal dementia and/or amyotrophic lateral sclerosis 6Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- adult-onset distal myopathy due to VCP mutationInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- amyotrophic lateral sclerosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- frontotemporal dementia with motor neuron diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- spastic paraplegia-Paget disease of bone syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- neurodevelopmental disorderInheritance: AD Classification: LIMITED Submitted by: G2P
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ACMG classification
Our verdict: Benign. The variant received -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VCP | NM_007126.5 | c.1704A>G | p.Gln568Gln | synonymous_variant | Exon 14 of 17 | ENST00000358901.11 | NP_009057.1 | |
VCP | NM_001354927.2 | c.1569A>G | p.Gln523Gln | synonymous_variant | Exon 14 of 17 | NP_001341856.1 | ||
VCP | NM_001354928.2 | c.1569A>G | p.Gln523Gln | synonymous_variant | Exon 14 of 17 | NP_001341857.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00297 AC: 451AN: 152076Hom.: 4 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00274 AC: 685AN: 250400 AF XY: 0.00258 show subpopulations
GnomAD4 exome AF: 0.00366 AC: 5346AN: 1461890Hom.: 6 Cov.: 32 AF XY: 0.00355 AC XY: 2585AN XY: 727246 show subpopulations
GnomAD4 genome AF: 0.00296 AC: 451AN: 152194Hom.: 4 Cov.: 32 AF XY: 0.00318 AC XY: 237AN XY: 74418 show subpopulations
ClinVar
Submissions by phenotype
not provided Benign:6
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VCP: BP4, BP7 -
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This variant is associated with the following publications: (PMID: 22137929, 25618255, 16790606) -
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not specified Benign:2
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Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 Benign:1
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. -
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
VCP-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Benign:1
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. -
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at