rs3816531

chr3-47006072-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015175.3(NBEAL2):c.6919+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0322 in 1,613,270 control chromosomes in the GnomAD database, including 2,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (357 hom., cov: 33)
  • Exomes 𝑓: 0.030 (2081 hom.)
• Consequence: NBEAL2 NM_015175.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.31

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 3-47006072-T-C is Benign according to our data. Variant chr3-47006072-T-C is described in ClinVar as [Benign]. Clinvar id is 260591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBEAL2	NM_015175.3	c.6919+9T>C		intron_variant		ENST00000450053.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBEAL2	ENST00000450053.8	c.6919+9T>C		intron_variant		2	NM_015175.3	P2

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7612 AN: 152150 Hom.: 353 Cov.: 33

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0506

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0663 AC: 16481 AN: 248612 Hom.: 1329 AF XY: 0.0575 AC XY: 7762 AN XY: 134962

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.0653

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.0440

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0471

GnomAD4 exome AF: 0.0304 AC: 44346 AN: 1461002 Hom.: 2081 Cov.: 34 AF XY: 0.0297 AC XY: 21583 AN XY: 726742

Gnomad4 AFR exome AF: 0.0767

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.0661

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.0421

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0341

GnomAD4 genome AF: 0.0501 AC: 7633 AN: 152268 Hom.: 357 Cov.: 33 AF XY: 0.0519 AC XY: 3861 AN XY: 74452

Gnomad4 AFR AF: 0.0761

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0649

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.0145

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0435

Alfa AF: 0.0394 Hom.: 62

Bravo AF: 0.0622

Asia WGS AF: 0.0650 AC: 225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 2019

- -

Gray platelet syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.69
Cadd	Benign	0.13
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs3816531; hg19: chr3-47047562; COSMIC: COSV52757124; COSMIC: COSV52757124;