rs751610198

Positions:

• chr2-27217892-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004341.5(CAD):​c.98T>G​(p.Met33Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAD NM_004341.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.02

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 Pathogenic. Variant got 15 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-27217892-T-G is Pathogenic according to our data. Variant chr2-27217892-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 374829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAD	NM_004341.5	c.98T>G	p.Met33Arg	missense_variant	2/44	ENST00000264705.9	NP_004332.2
CAD	NM_001306079.2	c.98T>G	p.Met33Arg	missense_variant	2/43		NP_001293008.1
CAD	XM_047445803.1	c.98T>G	p.Met33Arg	missense_variant	2/45		XP_047301759.1
CAD	XM_006712101.4	c.98T>G	p.Met33Arg	missense_variant	2/44		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAD	ENST00000264705.9	c.98T>G	p.Met33Arg	missense_variant	2/44	1	NM_004341.5	ENSP00000264705	P1
CAD	ENST00000403525.5	c.98T>G	p.Met33Arg	missense_variant	2/43	1		ENSP00000384510

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 243848 Hom.: 0 AF XY: 0.00000758 AC XY: 1 AN XY: 131962

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: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 33 of the CAD protein (p.Met33Arg). This variant is present in population databases (rs751610198, gnomAD 0.0009%). This missense change has been observed in individuals with CAD-related conditions (PMID: 28007989, 32461667, 32820246). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374829). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CAD function (PMID: 32461667). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2024	Published functional studies demonstrate a damaging effect on CAD activity (PMID: 32461667); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28007989, 32461667, 33249780, 32820246) -

Developmental and epileptic encephalopathy, 50 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 09, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.59	P;D
Vest4		0.86
MutPred		0.90		Gain of methylation at M33 (P = 0.0483);Gain of methylation at M33 (P = 0.0483);
MVP		0.93
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs751610198; hg19: chr2-27440760;