rs2234487

Variant names:

• chr20-58434740-C-T
• rs2234487
• NM_004738.5:c.315+35C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004738.5(VAPB):​c.315+35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,041,992 control chromosomes in the GnomAD database, including 92,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14311 hom., cov: 32)
  • Exomes 𝑓: 0.41 (78654 hom.)
• Consequence: VAPB NM_004738.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.731
• Publications: 14 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 20-58434740-C-T is Benign according to our data. Variant chr20-58434740-C-T is described in ClinVar as Benign. ClinVar VariationId is 259537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	NM_004738.5	MANE Select	c.315+35C>T		intron	N/A	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.212-9337C>T		intron	N/A	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.443-6167C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.315+35C>T		intron	N/A	ENSP00000417175.1	O95292-1
	VAPB	ENST00000395802.7	TSL:1	c.212-9337C>T		intron	N/A	ENSP00000379147.3	O95292-2
	VAPB	ENST00000903510.1		c.375+35C>T		intron	N/A	ENSP00000573569.1

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65360 AN: 151634 Hom.: 14302 Cov.: 32

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.396

GnomAD2 exomes AF: 0.413 AC: 99828 AN: 241560 AF XY: 0.416

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.572

Gnomad FIN exome AF: 0.531

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.411 AC: 365532 AN: 890238 Hom.: 78654 Cov.: 12 AF XY: 0.411 AC XY: 191803 AN XY: 466374

African (AFR) AF: 0.420 AC: 9392 AN: 22374

American (AMR) AF: 0.309 AC: 13484 AN: 43618

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 9295 AN: 22664

East Asian (EAS) AF: 0.631 AC: 23234 AN: 36830

South Asian (SAS) AF: 0.359 AC: 26686 AN: 74306

European-Finnish (FIN) AF: 0.518 AC: 25469 AN: 49148

Middle Eastern (MID) AF: 0.409 AC: 1757 AN: 4296

European-Non Finnish (NFE) AF: 0.402 AC: 239370 AN: 595422

Other (OTH) AF: 0.405 AC: 16845 AN: 41580

GnomAD4 genome AF: 0.431 AC: 65409 AN: 151754 Hom.: 14311 Cov.: 32 AF XY: 0.437 AC XY: 32416 AN XY: 74152

African (AFR) AF: 0.428 AC: 17705 AN: 41346

American (AMR) AF: 0.367 AC: 5588 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1452 AN: 3468

East Asian (EAS) AF: 0.586 AC: 3033 AN: 5180

South Asian (SAS) AF: 0.358 AC: 1721 AN: 4806

European-Finnish (FIN) AF: 0.549 AC: 5764 AN: 10494

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.423 AC: 28755 AN: 67912

Other (OTH) AF: 0.400 AC: 843 AN: 2110

Alfa AF: 0.428 Hom.: 2676

Bravo AF: 0.413

Asia WGS AF: 0.452 AC: 1567 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Adult-onset proximal spinal muscular atrophy, autosomal dominant (1)
-	-	1	Amyotrophic lateral sclerosis type 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.4
DANN	Benign	0.73
PhyloP100		0.73
Mutation Taster		=99/1	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: rs2234487; hg19: chr20-57009796; COSMIC: COSV55666732; COSMIC: COSV55666732;