11-17330136-C-G

Variant names:

• chr11-17330136-C-G
• rs757081
• NM_005013.4:c.1012C>G

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 68 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005013.4. 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
	NUCB2	NM_005013.4	MANE Select	c.1012C>G	p.Gln338Glu	missense	Exon 12 of 14	NP_005004.1	P80303-1
	NUCB2	NM_001352661.2		c.1015C>G	p.Gln339Glu	missense	Exon 14 of 16	NP_001339590.1
	NUCB2	NM_001352663.2		c.1015C>G	p.Gln339Glu	missense	Exon 13 of 15	NP_001339592.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUCB2	ENST00000529010.6	TSL:1 MANE Select	c.1012C>G	p.Gln338Glu	missense	Exon 12 of 14	ENSP00000436455.1	P80303-1
	NUCB2	ENST00000646648.1		n.*324C>G		non_coding_transcript_exon	Exon 14 of 17	ENSP00000495210.1	A0A2R8Y6G7
	NUCB2	ENST00000646648.1		n.*324C>G		3_prime_UTR	Exon 14 of 17	ENSP00000495210.1	A0A2R8Y6G7

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

GnomAD2 exomes AF: 0.302 AC: 61519 AN: 203674 AF XY: 0.304

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 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

African (AFR) AF: 0.0437 AC: 1329 AN: 30404

American (AMR) AF: 0.335 AC: 11400 AN: 34028

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7143 AN: 23550

East Asian (EAS) AF: 0.328 AC: 12528 AN: 38226

South Asian (SAS) AF: 0.304 AC: 22690 AN: 74574

European-Finnish (FIN) AF: 0.328 AC: 16922 AN: 51654

Middle Eastern (MID) AF: 0.220 AC: 1145 AN: 5214

European-Non Finnish (NFE) AF: 0.307 AC: 304292 AN: 991802

Other (OTH) AF: 0.285 AC: 15591 AN: 54688

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

African (AFR) AF: 0.0615 AC: 2545 AN: 41408

American (AMR) AF: 0.292 AC: 4458 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1074 AN: 3468

East Asian (EAS) AF: 0.351 AC: 1809 AN: 5160

South Asian (SAS) AF: 0.320 AC: 1540 AN: 4810

European-Finnish (FIN) AF: 0.313 AC: 3278 AN: 10476

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22363 AN: 67912

Other (OTH) AF: 0.270 AC: 569 AN: 2108

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 v4.9

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
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.072
Sift	Benign	0.37	T
Sift4G	Benign	0.69	T
Polyphen		0.054	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
Mutation Taster		=90/10	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: rs757081; hg19: chr11-17351683; COSMIC: COSV60373905; COSMIC: COSV60373905;