rs13066214

Variant names:

• chr3-46992447-C-T
• rs13066214
• NM_015175.3:c.1033-28C>T

Variant summary

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

The NM_015175.3(NBEAL2):​c.1033-28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,582,038 control chromosomes in the GnomAD database, including 249,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.49 (19432 hom., cov: 32)
  • Exomes 𝑓: 0.56 (230390 hom.)
• Consequence: NBEAL2 NM_015175.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.05
• Publications: 10 publications found

Genes affected

NBEAL2 (HGNC:31928): (neurobeachin like 2) The protein encoded by this gene contains a beige and Chediak-Higashi (BEACH) domain and multiple WD40 domains, and may play a role in megakaryocyte alpha-granule biogenesis. Mutations in this gene are a cause of gray platelet syndrome. [provided by RefSeq, Dec 2011]

NBEAL2 Gene-Disease associations (from GenCC):

• gray platelet syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-46992447-C-T is Benign according to our data. Variant chr3-46992447-C-T is described in ClinVar as Benign. ClinVar VariationId is 260575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015175.3. 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
	NBEAL2	NM_015175.3	MANE Select	c.1033-28C>T		intron	N/A	NP_055990.1	Q6ZNJ1-1
	NBEAL2	NM_001365116.2		c.1011+501C>T		intron	N/A	NP_001352045.1	A0A494C1V1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	ENST00000450053.8	TSL:2 MANE Select	c.1033-28C>T		intron	N/A	ENSP00000415034.2	Q6ZNJ1-1
	NBEAL2	ENST00000651747.1		c.1011+501C>T		intron	N/A	ENSP00000499216.1	A0A494C1V1
	NBEAL2	ENST00000933460.1		c.1032+501C>T		intron	N/A	ENSP00000603519.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73835 AN: 151922 Hom.: 19417 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.494

GnomAD2 exomes AF: 0.539 AC: 113991 AN: 211412 AF XY: 0.542

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.501

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.545

Gnomad FIN exome AF: 0.615

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.565 AC: 807379 AN: 1429998 Hom.: 230390 Cov.: 32 AF XY: 0.564 AC XY: 400143 AN XY: 709618

African (AFR) AF: 0.276 AC: 8965 AN: 32516

American (AMR) AF: 0.499 AC: 20936 AN: 41954

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 13264 AN: 25602

East Asian (EAS) AF: 0.566 AC: 21506 AN: 37992

South Asian (SAS) AF: 0.539 AC: 44348 AN: 82210

European-Finnish (FIN) AF: 0.607 AC: 31074 AN: 51220

Middle Eastern (MID) AF: 0.458 AC: 2562 AN: 5588

European-Non Finnish (NFE) AF: 0.578 AC: 632397 AN: 1093702

Other (OTH) AF: 0.546 AC: 32327 AN: 59214

GnomAD4 genome AF: 0.486 AC: 73882 AN: 152040 Hom.: 19432 Cov.: 32 AF XY: 0.486 AC XY: 36123 AN XY: 74320

African (AFR) AF: 0.282 AC: 11685 AN: 41468

American (AMR) AF: 0.490 AC: 7490 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1818 AN: 3470

East Asian (EAS) AF: 0.556 AC: 2859 AN: 5142

South Asian (SAS) AF: 0.541 AC: 2611 AN: 4822

European-Finnish (FIN) AF: 0.615 AC: 6516 AN: 10594

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39346 AN: 67946

Other (OTH) AF: 0.496 AC: 1046 AN: 2108

Alfa AF: 0.539 Hom.: 7247

Bravo AF: 0.467

Asia WGS AF: 0.594 AC: 2064 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Gray platelet syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.10
DANN	Benign	0.74
PhyloP100		-2.0
BranchPoint Hunter		1.0
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: rs13066214; hg19: chr3-47033937;