rs2024552

Variant names:

• chr20-58396314-G-T
• rs2024552
• NM_004738.5:c.58+6797G>T

Variant summary

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

The NM_004738.5(VAPB):​c.58+6797G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,002 control chromosomes in the GnomAD database, including 3,698 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 0.21 (3698 hom., cov: 32)
• Consequence: VAPB NM_004738.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.53
• Publications: 4 publications found

Genes affected

VAPB (HGNC:12649): (VAMP associated protein B and C) The protein encoded by this gene is a type IV membrane protein found in plasma and intracellular vesicle membranes. The encoded protein is found as a homodimer and as a heterodimer with VAPA. This protein also can interact with VAMP1 and VAMP2 and may be involved in vesicle trafficking. [provided by RefSeq, Jul 2008]

VAPB Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• adult-onset proximal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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 (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5	c.58+6797G>T		intron_variant	Intron 1 of 5	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.58+6797G>T		intron_variant	Intron 1 of 2		NP_001182606.1
VAPB	NR_036633.2	n.289+6797G>T		intron_variant	Intron 1 of 3
VAPB	XR_001754433.3	n.289+6797G>T		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.58+6797G>T		intron_variant	Intron 1 of 5	1	NM_004738.5	ENSP00000417175.1
VAPB	ENST00000395802.7	c.58+6797G>T		intron_variant	Intron 1 of 2	1		ENSP00000379147.3
VAPB	ENST00000265619.6	n.356+5974G>T		intron_variant	Intron 2 of 5	2
VAPB	ENST00000520497.1	n.58+6797G>T		intron_variant	Intron 1 of 3	2		ENSP00000430426.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31521 AN: 151886 Hom.: 3697 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.0869

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.207 AC: 31538 AN: 152002 Hom.: 3698 Cov.: 32 AF XY: 0.204 AC XY: 15179 AN XY: 74298

African (AFR) AF: 0.304 AC: 12595 AN: 41408

American (AMR) AF: 0.143 AC: 2179 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 625 AN: 3472

East Asian (EAS) AF: 0.0127 AC: 66 AN: 5180

South Asian (SAS) AF: 0.0864 AC: 416 AN: 4816

European-Finnish (FIN) AF: 0.202 AC: 2125 AN: 10540

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12866 AN: 67990

Other (OTH) AF: 0.182 AC: 384 AN: 2114

Alfa AF: 0.230 Hom.: 621

Bravo AF: 0.206

Asia WGS AF: 0.0850 AC: 296 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	0.14
DANN	Benign	0.31
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2024552; hg19: chr20-56971370;