NM_015175.3:c.6054C>G

Variant names:

• chr3-47004249-C-G
• rs1079276
• NM_015175.3:c.6054C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015175.3(NBEAL2):​c.6054C>G​(p.Pro2018Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,613,396 control chromosomes in the GnomAD database, including 254,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19430 hom., cov: 31)
  • Exomes 𝑓: 0.56 (235522 hom.)
• Consequence: NBEAL2 NM_015175.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.120
• Publications: 27 publications found

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]

NBEAL2 Gene-Disease associations (from GenCC):

• gray platelet syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.046).
• BP6: Variant 3-47004249-C-G is Benign according to our data. Variant chr3-47004249-C-G is described in ClinVar as Benign. ClinVar VariationId is 260586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015175.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	NM_015175.3	MANE Select	c.6054C>G	p.Pro2018Pro	synonymous	Exon 37 of 54	NP_055990.1
	NBEAL2	NM_001365116.2		c.5952C>G	p.Pro1984Pro	synonymous	Exon 36 of 53	NP_001352045.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	ENST00000450053.8	TSL:2 MANE Select	c.6054C>G	p.Pro2018Pro	synonymous	Exon 37 of 54	ENSP00000415034.2
	NBEAL2	ENST00000416683.5	TSL:1	c.3915C>G	p.Pro1305Pro	synonymous	Exon 23 of 40	ENSP00000410405.1
	NBEAL2	ENST00000443829.5	TSL:1	c.1158C>G	p.Pro386Pro	synonymous	Exon 7 of 23	ENSP00000414560.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73825 AN: 151820 Hom.: 19414 Cov.: 31

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.494

GnomAD2 exomes AF: 0.540 AC: 134582 AN: 249084 AF XY: 0.544

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.503

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.547

Gnomad FIN exome AF: 0.615

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.560

GnomAD4 exome AF: 0.565 AC: 825292 AN: 1461458 Hom.: 235522 Cov.: 79 AF XY: 0.564 AC XY: 410019 AN XY: 727010

African (AFR) AF: 0.278 AC: 9296 AN: 33474

American (AMR) AF: 0.501 AC: 22385 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 13546 AN: 26126

East Asian (EAS) AF: 0.566 AC: 22459 AN: 39700

South Asian (SAS) AF: 0.541 AC: 46631 AN: 86258

European-Finnish (FIN) AF: 0.607 AC: 32324 AN: 53254

Middle Eastern (MID) AF: 0.460 AC: 2652 AN: 5766

European-Non Finnish (NFE) AF: 0.578 AC: 642987 AN: 1111806

Other (OTH) AF: 0.547 AC: 33012 AN: 60362

GnomAD4 genome AF: 0.486 AC: 73872 AN: 151938 Hom.: 19430 Cov.: 31 AF XY: 0.486 AC XY: 36098 AN XY: 74256

African (AFR) AF: 0.283 AC: 11731 AN: 41440

American (AMR) AF: 0.490 AC: 7482 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1817 AN: 3472

East Asian (EAS) AF: 0.555 AC: 2852 AN: 5140

South Asian (SAS) AF: 0.541 AC: 2597 AN: 4802

European-Finnish (FIN) AF: 0.615 AC: 6503 AN: 10582

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39333 AN: 67914

Other (OTH) AF: 0.496 AC: 1046 AN: 2108

Alfa AF: 0.468 Hom.: 2585

Bravo AF: 0.468

Asia WGS AF: 0.593 AC: 2059 AN: 3478

EpiCase AF: 0.555

EpiControl AF: 0.559

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Gray platelet syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.6
DANN	Benign	0.48
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1079276; hg19: chr3-47045739; COSMIC: COSV52755488; COSMIC: COSV52755488;