dbSNP rs757081: NUCB2:p.Gln338Lys (chr11-17330136-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005013.4(NUCB2):c.1012C>A(p.Gln338Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000757 in 1,321,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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: not found (cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

NUCB2
NM_005013.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.26

Publications

0 publications found

Variant links:

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]

NUCB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34310418).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NUCB2	NM_005013.4	MANE Select	c.1012C>A	p.Gln338Lys	missense	Exon 12 of 14	NP_005004.1
NUCB2	NM_001352661.2		c.1015C>A	p.Gln339Lys	missense	Exon 14 of 16	NP_001339590.1
NUCB2	NM_001352663.2		c.1015C>A	p.Gln339Lys	missense	Exon 13 of 15	NP_001339592.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NUCB2	ENST00000529010.6	TSL:1 MANE Select	c.1012C>A	p.Gln338Lys	missense	Exon 12 of 14	ENSP00000436455.1
NUCB2	ENST00000646648.1		n.*324C>A		non_coding_transcript_exon	Exon 14 of 17	ENSP00000495210.1
NUCB2	ENST00000646648.1		n.*324C>A		3_prime_UTR	Exon 14 of 17	ENSP00000495210.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.57e-7

AC:

AN:

1321730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

658460

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30496

American (AMR)

AF:

0.00

AC:

AN:

34212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23720

East Asian (EAS)

AF:

0.00

AC:

AN:

38410

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5246

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1007608

Other (OTH)

AF:

0.00

AC:

AN:

55240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.012

MetaRNN

Benign

0.34

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.7

PhyloP100

4.3

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.5

REVEL

Benign

0.079

Sift

Benign

0.19

Sift4G

Benign

0.41

Polyphen

0.10

Vest4

0.28

MutPred

0.27

Gain of ubiquitination at Q338 (P = 0.0051)

MVP

0.17

MPC

0.14

ClinPred

0.78

GERP RS

5.7

Varity_R

0.17

gMVP

0.42

Mutation Taster

=76/24

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over