rs2258240

Variant names:

• chr9-35060958-T-C
• rs2258240
• NM_007126.5:c.1360-35A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-35060958-T-C
• chr9-35060958-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007126.5(VCP):​c.1360-35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.765 in 1,613,946 control chromosomes in the GnomAD database, including 475,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43403 hom., cov: 32)
  • Exomes 𝑓: 0.77 (432270 hom.)
• Consequence: VCP NM_007126.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.536
• Publications: 20 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae)
• frontotemporal dementia and/or amyotrophic lateral sclerosis 6

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-35060958-T-C is Benign according to our data. Variant chr9-35060958-T-C is described in ClinVar as Benign. ClinVar VariationId is 260123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.1360-35A>G		intron_variant	Intron 11 of 16	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.1225-35A>G		intron_variant	Intron 11 of 16		NP_001341856.1
VCP	NM_001354928.2	c.1225-35A>G		intron_variant	Intron 11 of 16		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.1360-35A>G		intron_variant	Intron 11 of 16	1	NM_007126.5	ENSP00000351777.6

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114391 AN: 151982 Hom.: 43374 Cov.: 32

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.752

GnomAD2 exomes AF: 0.748 AC: 188166 AN: 251462 AF XY: 0.746

Gnomad AFR exome AF: 0.742

Gnomad AMR exome AF: 0.844

Gnomad ASJ exome AF: 0.791

Gnomad EAS exome AF: 0.455

Gnomad FIN exome AF: 0.721

Gnomad NFE exome AF: 0.778

Gnomad OTH exome AF: 0.765

GnomAD4 exome AF: 0.767 AC: 1120704 AN: 1461846 Hom.: 432270 Cov.: 80 AF XY: 0.766 AC XY: 556761 AN XY: 727222

African (AFR) AF: 0.748 AC: 25033 AN: 33480

American (AMR) AF: 0.841 AC: 37621 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 20668 AN: 26136

East Asian (EAS) AF: 0.492 AC: 19534 AN: 39700

South Asian (SAS) AF: 0.713 AC: 61506 AN: 86250

European-Finnish (FIN) AF: 0.719 AC: 38401 AN: 53410

Middle Eastern (MID) AF: 0.747 AC: 4306 AN: 5764

European-Non Finnish (NFE) AF: 0.781 AC: 868196 AN: 1111986

Other (OTH) AF: 0.752 AC: 45439 AN: 60396

GnomAD4 genome AF: 0.753 AC: 114472 AN: 152100 Hom.: 43403 Cov.: 32 AF XY: 0.748 AC XY: 55622 AN XY: 74336

African (AFR) AF: 0.740 AC: 30674 AN: 41474

American (AMR) AF: 0.795 AC: 12156 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2762 AN: 3470

East Asian (EAS) AF: 0.462 AC: 2384 AN: 5160

South Asian (SAS) AF: 0.708 AC: 3411 AN: 4818

European-Finnish (FIN) AF: 0.719 AC: 7589 AN: 10562

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.780 AC: 53056 AN: 68016

Other (OTH) AF: 0.747 AC: 1572 AN: 2104

Alfa AF: 0.778 Hom.: 16326

Bravo AF: 0.759

Asia WGS AF: 0.584 AC: 2031 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2Y Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.93
DANN	Benign	0.54
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2258240; hg19: chr9-35060955; COSMIC: COSV62719666; COSMIC: COSV62719666;