rs1558524067

Variant names:

• chr2-27217594-C-G
• rs1558524067
• NM_004341.5:c.43C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-27217594-C-G
• chr2-27217594-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004341.5(CAD):​c.43C>G​(p.Gln15Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,456,672 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q15H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CAD NM_004341.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58
• Publications: 0 publications found

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]

CAD Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 50

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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=0.32118952).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004341.5. 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
	CAD	NM_004341.5	MANE Select	c.43C>G	p.Gln15Glu	missense	Exon 1 of 44	NP_004332.2
	CAD	NM_001306079.2		c.43C>G	p.Gln15Glu	missense	Exon 1 of 43	NP_001293008.1	F8VPD4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAD	ENST00000264705.9	TSL:1 MANE Select	c.43C>G	p.Gln15Glu	missense	Exon 1 of 44	ENSP00000264705.3	P27708
	CAD	ENST00000403525.5	TSL:1	c.43C>G	p.Gln15Glu	missense	Exon 1 of 43	ENSP00000384510.1	F8VPD4
	CAD	ENST00000854433.1		c.43C>G	p.Gln15Glu	missense	Exon 1 of 45	ENSP00000524492.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456672 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724330

African (AFR) AF: 0.00 AC: 0 AN: 33274

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39382

South Asian (SAS) AF: 0.00 AC: 0 AN: 85226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110132

Other (OTH) AF: 0.0000166 AC: 1 AN: 60088

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.0074
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	-1.1	N
PhyloP100		5.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.27
Sift	Benign	0.073	T
Sift4G	Benign	0.069	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.56		Loss of sheet (P = 0.0817)
MVP		0.60
MPC		0.38
ClinPred		0.66	D
GERP RS		4.4
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.33
gMVP		0.67
Mutation Taster		=89/11	polymorphism

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: rs1558524067; hg19: chr2-27440462;