NM_015175.3:c.1531C>G

Variant names:

• chr3-46995266-C-G
• rs11720139
• NM_015175.3:c.1531C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015175.3(NBEAL2):​c.1531C>G​(p.Arg511Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,559,560 control chromosomes in the GnomAD database, including 119,769 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R511H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (9478 hom., cov: 34)
  • Exomes 𝑓: 0.39 (110291 hom.)
• Consequence: NBEAL2 NM_015175.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.19
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003080964).
• BP6: Variant 3-46995266-C-G is Benign according to our data. Variant chr3-46995266-C-G is described in ClinVar as Benign. ClinVar VariationId is 260579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	NM_015175.3	MANE Select	c.1531C>G	p.Arg511Gly	missense	Exon 13 of 54	NP_055990.1
	NBEAL2	NM_001365116.2		c.1429C>G	p.Arg477Gly	missense	Exon 12 of 53	NP_001352045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	ENST00000450053.8	TSL:2 MANE Select	c.1531C>G	p.Arg511Gly	missense	Exon 13 of 54	ENSP00000415034.2
	NBEAL2	ENST00000651747.1		c.1429C>G	p.Arg477Gly	missense	Exon 12 of 53	ENSP00000499216.1
	NBEAL2	ENST00000933460.1		c.1450C>G	p.Arg484Gly	missense	Exon 12 of 52	ENSP00000603519.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52245 AN: 152044 Hom.: 9480 Cov.: 34

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.361 AC: 59658 AN: 165452 AF XY: 0.371

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.403

Gnomad EAS exome AF: 0.314

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.393 AC: 552504 AN: 1407398 Hom.: 110291 Cov.: 93 AF XY: 0.395 AC XY: 274429 AN XY: 695246

African (AFR) AF: 0.227 AC: 7261 AN: 31948

American (AMR) AF: 0.267 AC: 9827 AN: 36832

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 10346 AN: 25290

East Asian (EAS) AF: 0.289 AC: 10464 AN: 36242

South Asian (SAS) AF: 0.407 AC: 32730 AN: 80508

European-Finnish (FIN) AF: 0.374 AC: 17942 AN: 48004

Middle Eastern (MID) AF: 0.470 AC: 2679 AN: 5704

European-Non Finnish (NFE) AF: 0.404 AC: 438468 AN: 1084492

Other (OTH) AF: 0.390 AC: 22787 AN: 58378

GnomAD4 genome AF: 0.343 AC: 52243 AN: 152162 Hom.: 9478 Cov.: 34 AF XY: 0.346 AC XY: 25721 AN XY: 74396

African (AFR) AF: 0.230 AC: 9541 AN: 41532

American (AMR) AF: 0.334 AC: 5115 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1410 AN: 3472

East Asian (EAS) AF: 0.311 AC: 1605 AN: 5166

South Asian (SAS) AF: 0.396 AC: 1912 AN: 4828

European-Finnish (FIN) AF: 0.370 AC: 3920 AN: 10584

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27285 AN: 67964

Other (OTH) AF: 0.373 AC: 787 AN: 2112

Alfa AF: 0.295 Hom.: 1216

Bravo AF: 0.332

TwinsUK AF: 0.420 AC: 1557

ALSPAC AF: 0.395 AC: 1524

ESP6500AA AF: 0.202 AC: 789

ESP6500EA AF: 0.364 AC: 2983

ExAC AF: 0.280 AC: 30914

Asia WGS AF: 0.314 AC: 1093 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
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.024
Sift	Benign	0.29	T
Polyphen		0.094	B
Vest4		0.11
MPC		0.28
ClinPred		0.0041	T
GERP RS		4.5
PromoterAI		0.0089	Neutral
Varity_R		0.10
gMVP		0.26
Mutation Taster		=297/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11720139; hg19: chr3-47036756; COSMIC: COSV52755292; COSMIC: COSV52755292;