chr3-46995266-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015175.3(NBEAL2):c.1531C>G(p.Arg511Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,559,560 control chromosomes in the GnomAD database, including 119,769 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R511H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.34 ( 9478 hom., cov: 34)

Exomes 𝑓: 0.39 ( 110291 hom. )

Consequence

NBEAL2
NM_015175.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.19

Publications

34 publications found

Variant links:

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)

NBEAL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.003080964).

BP6

Variant 3-46995266-C-G is Benign according to our data. Variant chr3-46995266-C-G is described in ClinVar as Benign. ClinVar VariationId is 260579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL2	NM_015175.3 link	c.1531C>G	p.Arg511Gly	missense_variant	Exon 13 of 54	ENST00000450053.8	NP_055990.1	Q6ZNJ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NBEAL2	ENST00000450053.8 link	c.1531C>G	p.Arg511Gly	missense_variant	Exon 13 of 54	2	NM_015175.3	ENSP00000415034.2	Q6ZNJ1-1
NBEAL2	ENST00000651747.1 link	c.1429C>G	p.Arg477Gly	missense_variant	Exon 12 of 53			ENSP00000499216.1	A0A494C1V1
NBEAL2	ENST00000416683.5 link	c.-57C>G		upstream_gene_variant		1		ENSP00000410405.1	H0Y764

Frequencies

GnomAD3 genomes

AF:

0.344

AC:

52245

AN:

152044

Hom.:

9480

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.579

Gnomad AMR

AF:

0.334

Gnomad ASJ

AF:

0.406

Gnomad EAS

AF:

0.312

Gnomad SAS

AF:

0.396

Gnomad FIN

AF:

0.370

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.402

Gnomad OTH

AF:

0.374

GnomAD2 exomes

AF:

0.361

AC:

59658

AN:

165452

AF XY:

0.371

show subpopulations

Gnomad AFR exome

AF:

0.214

Gnomad AMR exome

AF:

0.252

Gnomad ASJ exome

AF:

0.403

Gnomad EAS exome

AF:

0.314

Gnomad FIN exome

AF:

0.364

Gnomad NFE exome

AF:

0.405

Gnomad OTH exome

AF:

0.376

GnomAD4 exome

AF:

0.393

AC:

552504

AN:

1407398

Hom.:

110291

Cov.:

AF XY:

0.395

AC XY:

274429

AN XY:

695246

show subpopulations

African (AFR)

AF:

0.227

AC:

7261

AN:

31948

American (AMR)

AF:

0.267

AC:

9827

AN:

36832

Ashkenazi Jewish (ASJ)

AF:

0.409

AC:

10346

AN:

25290

East Asian (EAS)

AF:

0.289

AC:

10464

AN:

36242

South Asian (SAS)

AF:

0.407

AC:

32730

AN:

80508

European-Finnish (FIN)

AF:

0.374

AC:

17942

AN:

48004

Middle Eastern (MID)

AF:

0.470

AC:

2679

AN:

5704

European-Non Finnish (NFE)

AF:

0.404

AC:

438468

AN:

1084492

Other (OTH)

AF:

0.390

AC:

22787

AN:

58378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

25486

50973

76459

101946

127432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13646

27292

40938

54584

68230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.343

AC:

52243

AN:

152162

Hom.:

9478

Cov.:

AF XY:

0.346

AC XY:

25721

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.230

AC:

9541

AN:

41532

American (AMR)

AF:

0.334

AC:

5115

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.406

AC:

1410

AN:

3472

East Asian (EAS)

AF:

0.311

AC:

1605

AN:

5166

South Asian (SAS)

AF:

0.396

AC:

1912

AN:

4828

European-Finnish (FIN)

AF:

0.370

AC:

3920

AN:

10584

Middle Eastern (MID)

AF:

0.483

AC:

142

AN:

294

European-Non Finnish (NFE)

AF:

0.401

AC:

27285

AN:

67964

Other (OTH)

AF:

0.373

AC:

787

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1838

3676

5513

7351

9189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

526

1052

1578

2104

2630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.295

Hom.:

1216

Bravo

AF:

0.332

TwinsUK

AF:

0.420

AC:

1557

ALSPAC

AF:

0.395

AC:

1524

ESP6500AA

AF:

0.202

AC:

789

ESP6500EA

AF:

0.364

AC:

2983

ExAC

AF:

0.280

AC:

30914

Asia WGS

AF:

0.314

AC:

1093

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Gray platelet syndrome

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.038

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.6

PhyloP100

1.2

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.7

REVEL

Benign

0.024

Sift

Benign

0.29

Polyphen

0.094

Vest4

0.11

MPC

0.28

ClinPred

0.0041

GERP RS

4.5

PromoterAI

0.0089

Neutral

(source)

Varity_R

0.10

gMVP

0.26

Mutation Taster

=297/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over