rs2258240

chr9-35060958-T-Cchr9-35060958-T-G

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: -0.536

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
VCP	NM_007126.5	c.1360-35A>G		intron_variant		ENST00000358901.11
VCP	NM_001354927.2	c.1225-35A>G		intron_variant
VCP	NM_001354928.2	c.1225-35A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCP	ENST00000358901.11	c.1360-35A>G		intron_variant		1	NM_007126.5	P3

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

GnomAD3 exomes AF: 0.748 AC: 188166 AN: 251462 Hom.: 71612 AF XY: 0.746 AC XY: 101417 AN XY: 135910

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 SAS exome AF: 0.709

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

Gnomad4 AFR exome AF: 0.748

Gnomad4 AMR exome AF: 0.841

Gnomad4 ASJ exome AF: 0.791

Gnomad4 EAS exome AF: 0.492

Gnomad4 SAS exome AF: 0.713

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.781

Gnomad4 OTH exome AF: 0.752

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

Gnomad4 AFR AF: 0.740

Gnomad4 AMR AF: 0.795

Gnomad4 ASJ AF: 0.796

Gnomad4 EAS AF: 0.462

Gnomad4 SAS AF: 0.708

Gnomad4 FIN AF: 0.719

Gnomad4 NFE AF: 0.780

Gnomad4 OTH AF: 0.747

Alfa AF: 0.777 Hom.: 9666

Bravo AF: 0.759

Asia WGS AF: 0.584 AC: 2031 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.93
Dann	Benign	0.54

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

Publications

LitVar

Other links and lift over

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