rs2268924

Variant names:

• chr20-58403122-A-G
• rs2268924
• NM_004738.5:c.58+13605A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-58403122-A-G
• chr20-58403122-A-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+13605A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 152,040 control chromosomes in the GnomAD database, including 8,860 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 0.33 (8860 hom., cov: 32)
• Consequence: VAPB NM_004738.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004738.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	NM_004738.5	MANE Select	c.58+13605A>G		intron	N/A	NP_004729.1
	VAPB	NM_001195677.2		c.58+13605A>G		intron	N/A	NP_001182606.1
	VAPB	NR_036633.2		n.289+13605A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.58+13605A>G		intron	N/A	ENSP00000417175.1
	VAPB	ENST00000395802.7	TSL:1	c.58+13605A>G		intron	N/A	ENSP00000379147.3
	VAPB	ENST00000265619.6	TSL:2	n.356+12782A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50912 AN: 151922 Hom.: 8857 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.291

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

GnomAD4 genome AF: 0.335 AC: 50932 AN: 152040 Hom.: 8860 Cov.: 32 AF XY: 0.341 AC XY: 25316 AN XY: 74312

African (AFR) AF: 0.346 AC: 14348 AN: 41474

American (AMR) AF: 0.213 AC: 3255 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1189 AN: 3460

East Asian (EAS) AF: 0.326 AC: 1680 AN: 5148

South Asian (SAS) AF: 0.330 AC: 1589 AN: 4816

European-Finnish (FIN) AF: 0.476 AC: 5026 AN: 10556

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22746 AN: 67988

Other (OTH) AF: 0.295 AC: 622 AN: 2112

Alfa AF: 0.348 Hom.: 1482

Bravo AF: 0.311

Asia WGS AF: 0.329 AC: 1141 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.63
PhyloP100		-1.2
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: rs2268924; hg19: chr20-56978178;