Genetic Variant VCP:c.*596C>T (chr9-35056521-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_007126.5(VCP):c.*596C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 161,934 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.013 ( 40 hom., cov: 33)

Exomes 𝑓: 0.012 ( 2 hom. )

Consequence

VCP
NM_007126.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.247

Publications

1 publications found

Variant links:

Genes affected

VCP (HGNC:12666): (valosin containing protein) This gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients. [provided by RefSeq, Aug 2017]

VCP Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
inclusion body myopathy with Paget disease of bone and frontotemporal dementia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Charcot-Marie-Tooth disease type 2Y
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
frontotemporal dementia and/or amyotrophic lateral sclerosis 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
adult-onset distal myopathy due to VCP mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
frontotemporal dementia with motor neuron disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spastic paraplegia-Paget disease of bone syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P

VCP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 9-35056521-G-A is Benign according to our data. Variant chr9-35056521-G-A is described in ClinVar as Benign. ClinVar VariationId is 366707.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1963/152324) while in subpopulation NFE AF = 0.0156 (1063/68034). AF 95% confidence interval is 0.0148. There are 40 homozygotes in GnomAd4. There are 1089 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1963 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007126.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VCP	NM_007126.5	MANE Select	c.*596C>T	3_prime_UTR	Exon 17 of 17	NP_009057.1	P55072
VCP	NM_001354927.2		c.*596C>T	3_prime_UTR	Exon 17 of 17	NP_001341856.1	C9JUP7
VCP	NM_001354928.2		c.*596C>T	3_prime_UTR	Exon 17 of 17	NP_001341857.1	C9JUP7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VCP	ENST00000358901.11	TSL:1 MANE Select	c.*596C>T	3_prime_UTR	Exon 17 of 17	ENSP00000351777.6	P55072
VCP	ENST00000940607.1		c.*596C>T	3_prime_UTR	Exon 17 of 17	ENSP00000610666.1
VCP	ENST00000969526.1		c.*596C>T	3_prime_UTR	Exon 17 of 17	ENSP00000639585.1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1963

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00936

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0603

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.00766

GnomAD4 exome

AF:

0.0118

AC:

113

AN:

9610

Hom.:

Cov.:

AF XY:

0.00995

AC XY:

AN XY:

5024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00306

AC:

AN:

1958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

548

South Asian (SAS)

AF:

0.00104

AC:

AN:

964

European-Finnish (FIN)

AF:

0.0513

AC:

AN:

526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0147

AC:

AN:

5040

Other (OTH)

AF:

0.0131

AC:

AN:

382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0129

AC:

1963

AN:

152324

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1089

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

41566

American (AMR)

AF:

0.00934

AC:

143

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00103

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0603

AC:

640

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0156

AC:

1063

AN:

68034

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

102

204

307

409

511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0129

Hom.:

Bravo

AF:

0.00783

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.52

PhyloP100

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over