3-47002048-C-T

Position:

• chr3-47002048-C-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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.90

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=-0.83).
• 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/exons	MANE	Protein	UniProt
NBEAL2	NM_015175.3	c.4911C>T	p.Ser1637Ser	synonymous_variant	31/54	ENST00000450053.8	NP_055990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBEAL2	ENST00000450053.8	c.4911C>T	p.Ser1637Ser	synonymous_variant	31/54	2	NM_015175.3	ENSP00000415034.2
NBEAL2	ENST00000416683.5	c.2772C>T	p.Ser924Ser	synonymous_variant	17/40	1		ENSP00000410405.1
NBEAL2	ENST00000443829.5	c.15C>T	p.Ser5Ser	synonymous_variant	1/23	1		ENSP00000414560.1
NBEAL2	ENST00000651747.1	c.4809C>T	p.Ser1603Ser	synonymous_variant	30/53			ENSP00000499216.1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73973 AN: 152008 Hom.: 19462 Cov.: 34

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

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.: 84 AF XY: 0.565 AC XY: 391718 AN XY: 693760

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.: 34 AF XY: 0.487 AC XY: 36187 AN XY: 74370

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

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -

Gray platelet syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	-0.83
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

Other links and lift over

dbSNP: rs2305634; hg19: chr3-47043538; COSMIC: COSV52754908; COSMIC: COSV52754908;