Genetic Variant NBEAL2:p.Arg511Cys (chr3-46995266-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_015175.3(NBEAL2):c.1531C>T(p.Arg511Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,559,732 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R511G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

NBEAL2
NM_015175.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021525621).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000716 (109/152202) while in subpopulation AFR AF = 0.00089 (37/41550). AF 95% confidence interval is 0.000664. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL2	NM_015175.3 link	c.1531C>T	p.Arg511Cys	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>T	p.Arg511Cys	missense_variant	Exon 13 of 54	2	NM_015175.3	ENSP00000415034.2	Q6ZNJ1-1
NBEAL2	ENST00000651747.1 link	c.1429C>T	p.Arg477Cys	missense_variant	Exon 12 of 53			ENSP00000499216.1	A0A494C1V1
NBEAL2	ENST00000416683.5 link	c.-57C>T		upstream_gene_variant		1		ENSP00000410405.1	H0Y764

Frequencies

GnomAD3 genomes

AF:

0.000717

AC:

109

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00576

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000671

AC:

111

AN:

165452

AF XY:

0.000583

show subpopulations

Gnomad AFR exome

AF:

0.000815

Gnomad AMR exome

AF:

0.0000387

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00607

Gnomad NFE exome

AF:

0.0000602

Gnomad OTH exome

AF:

0.000869

GnomAD4 exome

AF:

0.000225

AC:

316

AN:

1407530

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

143

AN XY:

695326

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

31948

American (AMR)

AF:

0.0000543

AC:

AN:

36848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25290

East Asian (EAS)

AF:

0.00

AC:

AN:

36244

South Asian (SAS)

AF:

0.00

AC:

AN:

80514

European-Finnish (FIN)

AF:

0.00506

AC:

243

AN:

48042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1084554

Other (OTH)

AF:

0.000154

AC:

AN:

58382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000716

AC:

109

AN:

152202

Hom.:

Cov.:

AF XY:

0.000954

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41550

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00576

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000332

Hom.:

1216

ExAC

AF:

0.000335

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

Eigen

Benign

0.015

Eigen_PC

Benign

-0.011

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.76

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

PhyloP100

1.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.9

REVEL

Benign

0.088

Sift

Benign

0.045

Polyphen

0.98

Vest4

0.32

MVP

0.082

MPC

0.50

ClinPred

0.017

GERP RS

4.5

PromoterAI

0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.32

Mutation Taster

=297/3

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over