rs2299612

Variant names:

• chr9-35070729-C-T
• rs2299612
• NM_007126.5:c.17+1608G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007126.5(VCP):​c.17+1608G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,200 control chromosomes in the GnomAD database, including 2,678 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2678 hom., cov: 32)
• Consequence: VCP NM_007126.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.425
• Publications: 5 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

ENSG00000288699 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.17+1608G>A		intron_variant	Intron 1 of 16	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.-119+1548G>A		intron_variant	Intron 1 of 16		NP_001341856.1
VCP	NM_001354928.2	c.-119+1028G>A		intron_variant	Intron 1 of 16		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.17+1608G>A		intron_variant	Intron 1 of 16	1	NM_007126.5	ENSP00000351777.6
ENSG00000288699	ENST00000681845.1	n.*116-2367G>A		intron_variant	Intron 1 of 4			ENSP00000505452.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26774 AN: 152082 Hom.: 2677 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.0788

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.181

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.176 AC: 26782 AN: 152200 Hom.: 2678 Cov.: 32 AF XY: 0.173 AC XY: 12866 AN XY: 74410

African (AFR) AF: 0.123 AC: 5113 AN: 41536

American (AMR) AF: 0.194 AC: 2960 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 988 AN: 3468

East Asian (EAS) AF: 0.0788 AC: 408 AN: 5178

South Asian (SAS) AF: 0.242 AC: 1169 AN: 4826

European-Finnish (FIN) AF: 0.103 AC: 1091 AN: 10612

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14351 AN: 67982

Other (OTH) AF: 0.181 AC: 384 AN: 2116

Alfa AF: 0.179 Hom.: 356

Bravo AF: 0.178

Asia WGS AF: 0.144 AC: 502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2299612; hg19: chr9-35070726;