chr3-46988740-C-G

Variant names:

• chr3-46988740-C-G
• rs61734084
• NM_015175.3:c.123C>G

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.123C>G​(p.Ser41Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,613,638 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: NBEAL2 NM_015175.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.208
• Publications: 2 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 (BayesDel_noAF=-0.43).
• BP6: Variant 3-46988740-C-G is Benign according to our data. Variant chr3-46988740-C-G is described in ClinVar as Benign. ClinVar VariationId is 345613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.208 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00313 (476/152318) while in subpopulation AFR AF = 0.0107 (445/41562). AF 95% confidence interval is 0.00989. There are 1 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	NM_015175.3	MANE Select	c.123C>G	p.Ser41Ser	synonymous	Exon 2 of 54	NP_055990.1	Q6ZNJ1-1
	NBEAL2	NM_001365116.2		c.102C>G	p.Ser34Ser	synonymous	Exon 2 of 53	NP_001352045.1	A0A494C1V1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBEAL2	ENST00000450053.8	TSL:2 MANE Select	c.123C>G	p.Ser41Ser	synonymous	Exon 2 of 54	ENSP00000415034.2	Q6ZNJ1-1
	NBEAL2	ENST00000651747.1		c.102C>G	p.Ser34Ser	synonymous	Exon 2 of 53	ENSP00000499216.1	A0A494C1V1
	NBEAL2	ENST00000933460.1		c.123C>G	p.Ser41Ser	synonymous	Exon 2 of 52	ENSP00000603519.1

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 474 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.000807 AC: 201 AN: 249110 AF XY: 0.000681

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000341 AC: 498 AN: 1461320 Hom.: 4 Cov.: 33 AF XY: 0.000275 AC XY: 200 AN XY: 726866

African (AFR) AF: 0.0115 AC: 384 AN: 33476

American (AMR) AF: 0.000805 AC: 36 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111558

Other (OTH) AF: 0.000961 AC: 58 AN: 60350

GnomAD4 genome AF: 0.00313 AC: 476 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00309 AC XY: 230 AN XY: 74492

African (AFR) AF: 0.0107 AC: 445 AN: 41562

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.00359

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Gray platelet syndrome (1)
-	-	1	NBEAL2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.8
DANN	Benign	0.82
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=298/2	polymorphism

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: rs61734084; hg19: chr3-47030230;