rs757081

Positions:

• chr11-17330136-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005013.4(NUCB2):​c.1012C>G​(p.Gln338Glu) variant causes a missense change. The variant allele was found at a frequency of 0.296 in 1,455,928 control chromosomes in the GnomAD database, including 66,585 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (5878 hom., cov: 32)
  • Exomes 𝑓: 0.30 (60707 hom.)
• Consequence: NUCB2 NM_005013.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.26

Genes affected

NUCB2 (HGNC:8044): (nucleobindin 2) This gene encodes a protein with a suggested role in calcium level maintenance, eating regulation in the hypothalamus, and release of tumor necrosis factor from vascular endothelial cells. This protein binds calcium and has EF-folding domains. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002201289).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUCB2	NM_005013.4	c.1012C>G	p.Gln338Glu	missense_variant	12/14	ENST00000529010.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUCB2	ENST00000529010.6	c.1012C>G	p.Gln338Glu	missense_variant	12/14	1	NM_005013.4	P3

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38125 AN: 151670 Hom.: 5881 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.268

GnomAD3 exomes AF: 0.302 AC: 61519 AN: 203674 Hom.: 9753 AF XY: 0.304 AC XY: 33755 AN XY: 110932

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.346

Gnomad SAS exome AF: 0.304

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.301 AC: 393040 AN: 1304140 Hom.: 60707 Cov.: 20 AF XY: 0.303 AC XY: 197153 AN XY: 650092

Gnomad4 AFR exome AF: 0.0437

Gnomad4 AMR exome AF: 0.335

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.328

Gnomad4 SAS exome AF: 0.304

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.251 AC: 38131 AN: 151788 Hom.: 5878 Cov.: 32 AF XY: 0.251 AC XY: 18649 AN XY: 74182

Gnomad4 AFR AF: 0.0615

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.329

Gnomad4 OTH AF: 0.270

Alfa AF: 0.317 Hom.: 6020

Bravo AF: 0.245

TwinsUK AF: 0.323 AC: 1196

ALSPAC AF: 0.336 AC: 1296

ESP6500AA AF: 0.0583 AC: 210

ESP6500EA AF: 0.320 AC: 2604

ExAC AF: 0.290 AC: 34912

Asia WGS AF: 0.300 AC: 1043 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.041	.;T;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;.;D;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;L;L;.
MutationTaster	Benign	0.000022	P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.080	N;N;.;N
REVEL	Benign	0.072
Sift	Benign	0.37	T;T;.;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.054	.;B;B;.
Vest4		0.13
MPC		0.12
ClinPred		0.0095	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.32

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: rs757081; hg19: chr11-17351683; COSMIC: COSV60373905; COSMIC: COSV60373905;