NM_004341.5:c.46C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004341.5(CAD):​c.46C>G​(p.Pro16Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CAD
NM_004341.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99
Variant links:
Genes affected
CAD (HGNC:1424): (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) The de novo synthesis of pyrimidine nucleotides is required for mammalian cells to proliferate. This gene encodes a trifunctional protein which is associated with the enzymatic activities of the first 3 enzymes in the 6-step pathway of pyrimidine biosynthesis: carbamoylphosphate synthetase (CPS II), aspartate transcarbamoylase, and dihydroorotase. This protein is regulated by the mitogen-activated protein kinase (MAPK) cascade, which indicates a direct link between activation of the MAPK cascade and de novo biosynthesis of pyrimidine nucleotides. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

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ACMG classification

Classification made for transcript

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=0.2521289).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CADNM_004341.5 linkc.46C>G p.Pro16Ala missense_variant Exon 1 of 44 ENST00000264705.9 NP_004332.2 P27708
CADNM_001306079.2 linkc.46C>G p.Pro16Ala missense_variant Exon 1 of 43 NP_001293008.1 P27708F8VPD4
CADXM_047445803.1 linkc.46C>G p.Pro16Ala missense_variant Exon 1 of 45 XP_047301759.1
CADXM_006712101.4 linkc.46C>G p.Pro16Ala missense_variant Exon 1 of 44 XP_006712164.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CADENST00000264705.9 linkc.46C>G p.Pro16Ala missense_variant Exon 1 of 44 1 NM_004341.5 ENSP00000264705.3 P27708
CADENST00000403525.5 linkc.46C>G p.Pro16Ala missense_variant Exon 1 of 43 1 ENSP00000384510.1 F8VPD4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jun 03, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CAD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 16 of the CAD protein (p.Pro16Ala). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Uncertain
0.030
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.27
T;T
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.25
T;T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
-1.7
N;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
0.32
N;N
REVEL
Benign
0.27
Sift
Benign
0.072
T;T
Sift4G
Benign
0.12
T;T
Polyphen
0.0010
B;B
Vest4
0.30
MutPred
0.64
Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP
0.52
MPC
0.34
ClinPred
0.70
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.087
gMVP
0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-27440465; API