rs2299612

chr9-35070729-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	UniProt
VCP	NM_007126.5	c.17+1608G>A		intron_variant		ENST00000358901.11
VCP	NM_001354927.2	c.-119+1548G>A		intron_variant
VCP	NM_001354928.2	c.-119+1028G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCP	ENST00000358901.11	c.17+1608G>A		intron_variant		1	NM_007126.5	P3

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

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.0788

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.181

Alfa AF: 0.181 Hom.: 349

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

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

LitVar

Other links and lift over

dbSNP: rs2299612; hg19: chr9-35070726;