rs140548682

Variant names:

• chr3-47003250-A-C
• rs140548682
• NM_015175.3:c.5661A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015175.3(NBEAL2):​c.5661A>C​(p.Pro1887Pro) 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
• Publications: 5 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=0.027).
• BP6: Variant 3-47003250-A-C is Benign according to our data. Variant chr3-47003250-A-C is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD gene

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.5661A>C	p.Pro1887Pro	synonymous	Exon 35 of 54	NP_055990.1
	NBEAL2	NM_001365116.2		c.5559A>C	p.Pro1853Pro	synonymous	Exon 34 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.5661A>C	p.Pro1887Pro	synonymous	Exon 35 of 54	ENSP00000415034.2
	NBEAL2	ENST00000416683.5	TSL:1	c.3522A>C	p.Pro1174Pro	synonymous	Exon 21 of 40	ENSP00000410405.1
	NBEAL2	ENST00000443829.5	TSL:1	c.765A>C	p.Pro255Pro	synonymous	Exon 5 of 23	ENSP00000414560.1

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

GnomAD2 exomes AF: 0.0144 AC: 3571 AN: 247976 AF XY: 0.0152

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 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

African (AFR) AF: 0.00293 AC: 98 AN: 33480

American (AMR) AF: 0.00597 AC: 267 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0213 AC: 1840 AN: 86248

European-Finnish (FIN) AF: 0.0185 AC: 976 AN: 52718

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.0225 AC: 25056 AN: 1111776

Other (OTH) AF: 0.0147 AC: 887 AN: 60362

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

African (AFR) AF: 0.00463 AC: 192 AN: 41440

American (AMR) AF: 0.0104 AC: 159 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.0210 AC: 101 AN: 4802

European-Finnish (FIN) AF: 0.0185 AC: 195 AN: 10562

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0201 AC: 1367 AN: 67962

Other (OTH) AF: 0.0128 AC: 27 AN: 2108

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Gray platelet syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.18
DANN	Benign	0.51
PhyloP100		-2.8
Mutation Taster		=100/0	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: rs140548682; hg19: chr3-47044740; COSMIC: COSV107345973; COSMIC: COSV107345973;