rs201015016

chr3-46992480-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_015175.3(NBEAL2):c.1038C>T(p.Tyr346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,605,408 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: NBEAL2 NM_015175.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.12

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-46992480-C-T is Benign according to our data. Variant chr3-46992480-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 435924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46992480-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00193 (294/152116) while in subpopulation NFE AF= 0.00328 (223/67980). AF 95% confidence interval is 0.00293. There are 1 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBEAL2	NM_015175.3	c.1038C>T	p.Tyr346=	synonymous_variant	10/54	ENST00000450053.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBEAL2	ENST00000450053.8	c.1038C>T	p.Tyr346=	synonymous_variant	10/54	2	NM_015175.3	P2
NBEAL2	ENST00000651747.1	c.1011+534C>T		intron_variant				A2

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 151998 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00191 AC: 446 AN: 233492 Hom.: 0 AF XY: 0.00183 AC XY: 233 AN XY: 127122

Gnomad AFR exome AF: 0.000523

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00178

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000533

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.00263 AC: 3822 AN: 1453292 Hom.: 7 Cov.: 32 AF XY: 0.00254 AC XY: 1834 AN XY: 722144

Gnomad4 AFR exome AF: 0.000603

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.00143

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000706

Gnomad4 NFE exome AF: 0.00317

Gnomad4 OTH exome AF: 0.00241

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152116 Hom.: 1 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74380

Gnomad4 AFR AF: 0.000531

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 19, 2017

- -

NBEAL2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2018

- -

Gray platelet syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.7
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs201015016; hg19: chr3-47033970;