Genetic Variant NBEAL2:p.Ser1637Ser (chr3-47002048-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015175.3(NBEAL2):c.4911C>T(p.Ser1637Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,556,712 control chromosomes in the GnomAD database, including 246,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 19478 hom., cov: 34)

Exomes 𝑓: 0.57 ( 226867 hom. )

Consequence

NBEAL2
NM_015175.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.90

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 3-47002048-C-T is Benign according to our data. Variant chr3-47002048-C-T is described in ClinVar as [Benign]. Clinvar id is 260582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47002048-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.9 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL2	NM_015175.3 link	c.4911C>T	p.Ser1637Ser	synonymous_variant	Exon 31 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.4911C>T	p.Ser1637Ser	synonymous_variant	Exon 31 of 54	2	NM_015175.3	ENSP00000415034.2		Q6ZNJ1-1

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

73973

AN:

152008

Hom.:

19462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.283

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.490

Gnomad ASJ

AF:

0.524

Gnomad EAS

AF:

0.556

Gnomad SAS

AF:

0.542

Gnomad FIN

AF:

0.615

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.579

Gnomad OTH

AF:

0.496

GnomAD3 exomes

AF:

0.544

AC:

88049

AN:

162000

Hom.:

24419

AF XY:

0.546

AC XY:

47571

AN XY:

87170

show subpopulations

Gnomad AFR exome

AF:

0.288

Gnomad AMR exome

AF:

0.503

Gnomad ASJ exome

AF:

0.524

Gnomad EAS exome

AF:

0.550

Gnomad SAS exome

AF:

0.537

Gnomad FIN exome

AF:

0.617

Gnomad NFE exome

AF:

0.577

Gnomad OTH exome

AF:

0.551

GnomAD4 exome

AF:

0.565

AC:

794022

AN:

1404586

Hom.:

226867

Cov.:

AF XY:

0.565

AC XY:

391718

AN XY:

693760

show subpopulations

Gnomad4 AFR exome

AF:

0.277

Gnomad4 AMR exome

AF:

0.499

Gnomad4 ASJ exome

AF:

0.518

Gnomad4 EAS exome

AF:

0.568

Gnomad4 SAS exome

AF:

0.540

Gnomad4 FIN exome

AF:

0.607

Gnomad4 NFE exome

AF:

0.579

Gnomad4 OTH exome

AF:

0.545

GnomAD4 genome

AF:

0.487

AC:

74020

AN:

152126

Hom.:

19478

Cov.:

AF XY:

0.487

AC XY:

36187

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.284

Gnomad4 AMR

AF:

0.490

Gnomad4 ASJ

AF:

0.524

Gnomad4 EAS

AF:

0.556

Gnomad4 SAS

AF:

0.542

Gnomad4 FIN

AF:

0.615

Gnomad4 NFE

AF:

0.579

Gnomad4 OTH

AF:

0.498

Alfa

AF:

0.533

Hom.:

14296

Bravo

AF:

0.468

Asia WGS

AF:

0.593

AC:

2058

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

not provided

Benign:2

Oct 23, 2020

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

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.74

DANN

Benign

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over