chr2-27217596-G-T

Position:

• chr2-27217596-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004341.5(CAD):​c.45G>T​(p.Gln15His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CAD. . Gene score misZ 4.3365 (greater than the threshold 3.09). Trascript score misZ 5.7639 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 50.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2738906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAD	NM_004341.5	c.45G>T	p.Gln15His	missense_variant	1/44	ENST00000264705.9	NP_004332.2
CAD	NM_001306079.2	c.45G>T	p.Gln15His	missense_variant	1/43		NP_001293008.1
CAD	XM_047445803.1	c.45G>T	p.Gln15His	missense_variant	1/45		XP_047301759.1
CAD	XM_006712101.4	c.45G>T	p.Gln15His	missense_variant	1/44		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAD	ENST00000264705.9	c.45G>T	p.Gln15His	missense_variant	1/44	1	NM_004341.5	ENSP00000264705.3
CAD	ENST00000403525.5	c.45G>T	p.Gln15His	missense_variant	1/43	1		ENSP00000384510.1

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 15 of the CAD protein (p.Gln15His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CAD-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CAD protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.24
Sift	Benign	0.074	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.043	B;B
Vest4		0.30
MutPred		0.42		Gain of methylation at R13 (P = 0.0547);Gain of methylation at R13 (P = 0.0547);
MVP		0.64
MPC		0.33
ClinPred		0.48	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.23
gMVP		0.78

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: chr2-27440464;