chr2-27232672-G-C

Variant names:

• chr2-27232672-G-C
• NM_004341.5:c.2870G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004341.5(CAD):​c.2870G>C​(p.Gly957Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAD NM_004341.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.05

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAD	NM_004341.5	c.2870G>C	p.Gly957Ala	missense_variant	Exon 18 of 44	ENST00000264705.9	NP_004332.2
CAD	NM_001306079.2	c.2681G>C	p.Gly894Ala	missense_variant	Exon 17 of 43		NP_001293008.1
CAD	XM_047445803.1	c.2870G>C	p.Gly957Ala	missense_variant	Exon 18 of 45		XP_047301759.1
CAD	XM_006712101.4	c.2681G>C	p.Gly894Ala	missense_variant	Exon 17 of 44		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAD	ENST00000264705.9	c.2870G>C	p.Gly957Ala	missense_variant	Exon 18 of 44	1	NM_004341.5	ENSP00000264705.3
CAD	ENST00000403525.5	c.2681G>C	p.Gly894Ala	missense_variant	Exon 17 of 43	1		ENSP00000384510.1
CAD	ENST00000464159.1	n.*29G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.17	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.94	P;B
Vest4		0.81
MutPred		0.59		Gain of helix (P = 0.132);.;
MVP		0.89
MPC		2.0
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.50
gMVP		0.92

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: chr2-27455540;