3-47001748-C-T

Variant names:

• chr3-47001748-C-T
• rs12489851
• NM_015175.3:c.4704C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015175.3(NBEAL2):​c.4704C>T​(p.Asn1568Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,894 control chromosomes in the GnomAD database, including 2,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (226 hom., cov: 33)
  • Exomes 𝑓: 0.028 (1955 hom.)
• Consequence: NBEAL2 NM_015175.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.83

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-47001748-C-T is Benign according to our data. Variant chr3-47001748-C-T is described in ClinVar as [Benign]. Clinvar id is 260580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL2	NM_015175.3	c.4704C>T	p.Asn1568Asn	synonymous_variant	Exon 30 of 54	ENST00000450053.8	NP_055990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBEAL2	ENST00000450053.8	c.4704C>T	p.Asn1568Asn	synonymous_variant	Exon 30 of 54	2	NM_015175.3	ENSP00000415034.2
NBEAL2	ENST00000416683.5	c.2565C>T	p.Asn855Asn	synonymous_variant	Exon 16 of 40	1		ENSP00000410405.1
NBEAL2	ENST00000651747.1	c.4602C>T	p.Asn1534Asn	synonymous_variant	Exon 29 of 53			ENSP00000499216.1
NBEAL2	ENST00000475689.1	n.549C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4621 AN: 152188 Hom.: 226 Cov.: 33

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0494

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0612 AC: 15251 AN: 249078 Hom.: 1263 AF XY: 0.0538 AC XY: 7271 AN XY: 135192

Gnomad AFR exome AF: 0.00808

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.0440

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0283 AC: 41363 AN: 1461588 Hom.: 1955 Cov.: 31 AF XY: 0.0280 AC XY: 20342 AN XY: 727064

Gnomad4 AFR exome AF: 0.00621

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.0421

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0296

GnomAD4 genome AF: 0.0304 AC: 4629 AN: 152306 Hom.: 226 Cov.: 33 AF XY: 0.0331 AC XY: 2465 AN XY: 74456

Gnomad4 AFR AF: 0.00768

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.0617

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.0495

Gnomad4 FIN AF: 0.0145

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0292 Hom.: 141

Bravo AF: 0.0397

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0190

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gray platelet syndrome Benign:1

Jan 12, 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	-0.68
CADD	Benign	1.0
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs12489851; hg19: chr3-47043238; COSMIC: COSV52755552; COSMIC: COSV52755552;