chr19-48919235-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006184.6(NUCB1):ā€‹c.951C>Gā€‹(p.Phe317Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000075 ( 0 hom. )

Consequence

NUCB1
NM_006184.6 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31
Variant links:
Genes affected
NUCB1 (HGNC:8043): (nucleobindin 1) This gene encodes a member of a small calcium-binding EF-hand protein family. The encoded protein is thought to have a key role in Golgi calcium homeostasis and Ca(2+)-regulated signal transduction events. [provided by RefSeq, Jun 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NUCB1NM_006184.6 linkuse as main transcriptc.951C>G p.Phe317Leu missense_variant 10/13 ENST00000405315.9 NP_006175.2
NUCB1XM_017026845.2 linkuse as main transcriptc.951C>G p.Phe317Leu missense_variant 10/13 XP_016882334.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NUCB1ENST00000405315.9 linkuse as main transcriptc.951C>G p.Phe317Leu missense_variant 10/131 NM_006184.6 ENSP00000385923 P2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251322
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461738
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727178
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 06, 2022The c.951C>G (p.F317L) alteration is located in exon 10 (coding exon 9) of the NUCB1 gene. This alteration results from a C to G substitution at nucleotide position 951, causing the phenylalanine (F) at amino acid position 317 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.36
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D
Eigen
Benign
-0.012
Eigen_PC
Benign
-0.078
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.93
D;.
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Pathogenic
3.4
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.7
D;D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.18
T;T
Polyphen
1.0
D;D
Vest4
0.96
MutPred
0.63
Gain of phosphorylation at S320 (P = 0.1524);Gain of phosphorylation at S320 (P = 0.1524);
MVP
0.93
MPC
1.1
ClinPred
0.95
D
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.88
gMVP
0.87

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757681738; hg19: chr19-49422492; API