Genetic Variant VCP:c.1082-18_1082-8dupTTGTGTACTGT (chr9-35061696-G-GACAGTACACAA) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_007126.5(VCP):c.1082-18_1082-8dupTTGTGTACTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,589,212 control chromosomes in the GnomAD database, including 354,099 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 25664 hom., cov: 0)

Exomes 𝑓: 0.66 ( 328435 hom. )

Consequence

VCP
NM_007126.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.10

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 9-35061696-G-GACAGTACACAA is Benign according to our data. Variant chr9-35061696-G-GACAGTACACAA is described in ClinVar as [Benign]. Clinvar id is 260119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
VCP	NM_007126.5 link	c.1082-18_1082-8dupTTGTGTACTGT	splice_region_variant, intron_variant	Intron 9 of 16	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2 link	c.947-18_947-8dupTTGTGTACTGT	splice_region_variant, intron_variant	Intron 9 of 16		NP_001341856.1
VCP	NM_001354928.2 link	c.947-18_947-8dupTTGTGTACTGT	splice_region_variant, intron_variant	Intron 9 of 16		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11 link	c.1082-8_1082-7insTTGTGTACTGT		splice_region_variant, intron_variant	Intron 9 of 16	1	NM_007126.5	ENSP00000351777.6		P55072

Frequencies

GnomAD3 genomes

AF:

0.544

AC:

82335

AN:

151418

Hom.:

25652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.271

Gnomad AMI

AF:

0.684

Gnomad AMR

AF:

0.654

Gnomad ASJ

AF:

0.656

Gnomad EAS

AF:

0.0833

Gnomad SAS

AF:

0.480

Gnomad FIN

AF:

0.605

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.706

Gnomad OTH

AF:

0.583

GnomAD4 exome

AF:

0.659

AC:

947640

AN:

1437676

Hom.:

328435

Cov.:

AF XY:

0.656

AC XY:

470496

AN XY:

716972

show subpopulations

Gnomad4 AFR exome

AF:

0.251

Gnomad4 AMR exome

AF:

0.663

Gnomad4 ASJ exome

AF:

0.651

Gnomad4 EAS exome

AF:

0.0684

Gnomad4 SAS exome

AF:

0.502

Gnomad4 FIN exome

AF:

0.607

Gnomad4 NFE exome

AF:

0.711

Gnomad4 OTH exome

AF:

0.616

GnomAD4 genome

AF:

0.544

AC:

82379

AN:

151536

Hom.:

25664

Cov.:

AF XY:

0.538

AC XY:

39815

AN XY:

74046

show subpopulations

Gnomad4 AFR

AF:

0.271

Gnomad4 AMR

AF:

0.654

Gnomad4 ASJ

AF:

0.656

Gnomad4 EAS

AF:

0.0835

Gnomad4 SAS

AF:

0.481

Gnomad4 FIN

AF:

0.605

Gnomad4 NFE

AF:

0.706

Gnomad4 OTH

AF:

0.581

Alfa

AF:

0.612

Hom.:

4986

Asia WGS

AF:

0.301

AC:

1053

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 14, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 2019

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

VCP-related disorder

Benign:1

Mar 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Amyotrophic Lateral Sclerosis, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inclusion Body Myopathy, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

9-35061696-GACAGTACACAA-GACAGTACACAAACAGTACACAA

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