3-47002048-C-T

Variant names:

• chr3-47002048-C-T
• rs2305634
• NM_015175.3:c.4911C>T

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.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
• Publications: 23 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=0.057).
• BP6: Variant 3-47002048-C-T is Benign according to our data. Variant chr3-47002048-C-T is described in ClinVar as Benign. ClinVar VariationId is 260582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.4911C>T	p.Ser1637Ser	synonymous	Exon 31 of 54	NP_055990.1
	NBEAL2	NM_001365116.2		c.4809C>T	p.Ser1603Ser	synonymous	Exon 30 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.4911C>T	p.Ser1637Ser	synonymous	Exon 31 of 54	ENSP00000415034.2
	NBEAL2	ENST00000416683.5	TSL:1	c.2772C>T	p.Ser924Ser	synonymous	Exon 17 of 40	ENSP00000410405.1
	NBEAL2	ENST00000443829.5	TSL:1	c.15C>T	p.Ser5Ser	synonymous	Exon 1 of 23	ENSP00000414560.1

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

GnomAD2 exomes AF: 0.544 AC: 88049 AN: 162000 AF XY: 0.546

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 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

African (AFR) AF: 0.277 AC: 8839 AN: 31876

American (AMR) AF: 0.499 AC: 17982 AN: 36008

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 13085 AN: 25238

East Asian (EAS) AF: 0.568 AC: 20470 AN: 36068

South Asian (SAS) AF: 0.540 AC: 43519 AN: 80556

European-Finnish (FIN) AF: 0.607 AC: 29277 AN: 48258

Middle Eastern (MID) AF: 0.459 AC: 2618 AN: 5700

European-Non Finnish (NFE) AF: 0.579 AC: 626487 AN: 1082624

Other (OTH) AF: 0.545 AC: 31745 AN: 58258

GnomAD4 genome AF: 0.487 AC: 74020 AN: 152126 Hom.: 19478 Cov.: 34 AF XY: 0.487 AC XY: 36187 AN XY: 74370

African (AFR) AF: 0.284 AC: 11769 AN: 41508

American (AMR) AF: 0.490 AC: 7494 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1817 AN: 3470

East Asian (EAS) AF: 0.556 AC: 2874 AN: 5168

South Asian (SAS) AF: 0.542 AC: 2614 AN: 4826

European-Finnish (FIN) AF: 0.615 AC: 6513 AN: 10584

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

European-Non Finnish (NFE) AF: 0.579 AC: 39378 AN: 67960

Other (OTH) AF: 0.498 AC: 1050 AN: 2108

Alfa AF: 0.535 Hom.: 19160

Bravo AF: 0.468

Asia WGS AF: 0.593 AC: 2058 AN: 3478

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	-0.83
CADD	Benign	0.74
DANN	Benign	0.45
PhyloP100		-1.9
PromoterAI		-0.017	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

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