chr3-47004356-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP3BP4_StrongBP6_Very_StrongBA1

The NM_015175.3(NBEAL2):c.6161C>T(p.Ser2054Phe) variant causes a missense change. The variant allele was found at a frequency of 0.164 in 1,602,398 control chromosomes in the GnomAD database, including 22,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1827 hom., cov: 32)

Exomes 𝑓: 0.17 ( 21107 hom. )

Consequence

NBEAL2
NM_015175.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.90

Publications

40 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 -17 ACMG points.

PM1

In a domain BEACH (size 292) in uniprot entity NBEL2_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_015175.3

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0017380118).

BP6

Variant 3-47004356-C-T is Benign according to our data. Variant chr3-47004356-C-T is described in CliVar as Benign. Clinvar id is 260587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47004356-C-T is described in CliVar as Benign. Clinvar id is 260587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47004356-C-T is described in CliVar as Benign. Clinvar id is 260587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47004356-C-T is described in CliVar as Benign. Clinvar id is 260587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47004356-C-T is described in CliVar as Benign. Clinvar id is 260587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47004356-C-T is described in CliVar as Benign. Clinvar id is 260587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47004356-C-T is described in CliVar as Benign. Clinvar id is 260587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47004356-C-T is described in CliVar as Benign. Clinvar id is 260587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL2	NM_015175.3 link	c.6161C>T	p.Ser2054Phe	missense_variant	Exon 37 of 54	ENST00000450053.8	NP_055990.1	Q6ZNJ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBEAL2	ENST00000450053.8 link	c.6161C>T	p.Ser2054Phe	missense_variant	Exon 37 of 54	2	NM_015175.3	ENSP00000415034.2		Q6ZNJ1-1

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20874

AN:

151822

Hom.:

1826

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0409

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.0980

Gnomad EAS

AF:

0.224

Gnomad SAS

AF:

0.0929

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.160

GnomAD2 exomes

AF:

0.155

AC:

37011

AN:

239496

AF XY:

0.154

show subpopulations

Gnomad AFR exome

AF:

0.0368

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.0980

Gnomad EAS exome

AF:

0.228

Gnomad FIN exome

AF:

0.237

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.172

GnomAD4 exome

AF:

0.166

AC:

241344

AN:

1450458

Hom.:

21107

Cov.:

AF XY:

0.164

AC XY:

118281

AN XY:

720286

show subpopulations

African (AFR)

AF:

0.0370

AC:

1235

AN:

33338

American (AMR)

AF:

0.127

AC:

5638

AN:

44270

Ashkenazi Jewish (ASJ)

AF:

0.0914

AC:

2308

AN:

25250

East Asian (EAS)

AF:

0.219

AC:

8653

AN:

39594

South Asian (SAS)

AF:

0.0977

AC:

8271

AN:

84646

European-Finnish (FIN)

AF:

0.234

AC:

12318

AN:

52550

Middle Eastern (MID)

AF:

0.134

AC:

765

AN:

5720

European-Non Finnish (NFE)

AF:

0.174

AC:

192826

AN:

1105166

Other (OTH)

AF:

0.156

AC:

9330

AN:

59924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

12526

25052

37579

50105

62631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6740

13480

20220

26960

33700

<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:

0.137

AC:

20867

AN:

151940

Hom.:

1827

Cov.:

AF XY:

0.140

AC XY:

10385

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.0408

AC:

1694

AN:

41470

American (AMR)

AF:

0.150

AC:

2288

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0980

AC:

340

AN:

3470

East Asian (EAS)

AF:

0.224

AC:

1151

AN:

5132

South Asian (SAS)

AF:

0.0927

AC:

446

AN:

4810

European-Finnish (FIN)

AF:

0.243

AC:

2561

AN:

10550

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.175

AC:

11867

AN:

67920

Other (OTH)

AF:

0.158

AC:

334

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

874

1749

2623

3498

4372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.157

Hom.:

2346

Bravo

AF:

0.129

TwinsUK

AF:

0.177

AC:

655

ALSPAC

AF:

0.167

AC:

644

ESP6500AA

AF:

0.0466

AC:

185

ESP6500EA

AF:

0.168

AC:

1392

ExAC

AF:

0.151

AC:

18307

Asia WGS

AF:

0.165

AC:

576

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

Jun 09, 2021

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:1

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

Pathogenic

0.62

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.9

PhyloP100

5.9

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Polyphen

0.99

Vest4

0.26

MPC

1.4

ClinPred

0.036

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.83

gMVP

0.76

Mutation Taster

=81/19

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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