rs140548682

Positions:

• chr3-47003250-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015175.3(NBEAL2):​c.5661A>C​(p.Pro1887=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,612,880 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.020 (345 hom.)
• Consequence: NBEAL2 NM_015175.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.79

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=-0.82).
• BP6: Variant 3-47003250-A-C is Benign according to our data. Variant chr3-47003250-A-C is described in ClinVar as [Benign]. Clinvar id is 260585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0137 (2079/151990) while in subpopulation SAS AF= 0.021 (101/4802). AF 95% confidence interval is 0.0192. There are 22 homozygotes in gnomad4. There are 1062 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBEAL2	NM_015175.3	c.5661A>C	p.Pro1887=	synonymous_variant	35/54	ENST00000450053.8	NP_055990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBEAL2	ENST00000450053.8	c.5661A>C	p.Pro1887=	synonymous_variant	35/54	2	NM_015175.3	ENSP00000415034	P2
NBEAL2	ENST00000416683.5	c.3525A>C	p.Pro1175=	synonymous_variant	21/40	1		ENSP00000410405
NBEAL2	ENST00000443829.5	c.768A>C	p.Pro256=	synonymous_variant	5/23	1		ENSP00000414560
NBEAL2	ENST00000651747.1	c.5559A>C	p.Pro1853=	synonymous_variant	34/53			ENSP00000499216	A2

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2078 AN: 151874 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00465

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0206

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0144 AC: 3571 AN: 247976 Hom.: 45 AF XY: 0.0152 AC XY: 2048 AN XY: 134898

Gnomad AFR exome AF: 0.00325

Gnomad AMR exome AF: 0.00577

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0200 AC: 29243 AN: 1460890 Hom.: 345 Cov.: 34 AF XY: 0.0200 AC XY: 14518 AN XY: 726702

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.00597

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.0185

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0137 AC: 2079 AN: 151990 Hom.: 22 Cov.: 32 AF XY: 0.0143 AC XY: 1062 AN XY: 74304

Gnomad4 AFR AF: 0.00463

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0210

Gnomad4 FIN AF: 0.0185

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0163 Hom.: 8

Bravo AF: 0.0119

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0176

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Gray platelet syndrome Benign:1

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	-0.82
CADD	Benign	0.18
DANN	Benign	0.51

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: rs140548682; hg19: chr3-47044740;