3-46995266-C-A

Position:

• chr3-46995266-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015175.3(NBEAL2):​c.1531C>A​(p.Arg511Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000577 in 1,559,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R511G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NBEAL2 NM_015175.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22083762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBEAL2	NM_015175.3	c.1531C>A	p.Arg511Ser	missense_variant	13/54	ENST00000450053.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBEAL2	ENST00000450053.8	c.1531C>A	p.Arg511Ser	missense_variant	13/54	2	NM_015175.3	P2
NBEAL2	ENST00000651747.1	c.1429C>A	p.Arg477Ser	missense_variant	12/53			A2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152084 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1407530 Hom.: 0 Cov.: 93 AF XY: 0.00 AC XY: 0 AN XY: 695326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152084 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.46
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.13	P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.026
Sift	Benign	0.55	T
Polyphen		0.049	B
Vest4		0.15
MutPred		0.34		Gain of disorder (P = 0.1519);
MVP		0.21
MPC		0.24
ClinPred		0.21	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs11720139; hg19: chr3-47036756;