NM_004341.5:c.2288-1552T>C

Variant names:

• chr2-27229916-T-C
• rs6717980
• NM_004341.5:c.2288-1552T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004341.5(CAD):​c.2288-1552T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 148,558 control chromosomes in the GnomAD database, including 17,525 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (17525 hom., cov: 29)
• Consequence: CAD NM_004341.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321
• Publications: 8 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: Illumina, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAD	NM_004341.5	MANE Select	c.2288-1552T>C		intron	N/A	NP_004332.2
	CAD	NM_001306079.2		c.2099-1552T>C		intron	N/A	NP_001293008.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAD	ENST00000264705.9	TSL:1 MANE Select	c.2288-1552T>C		intron	N/A	ENSP00000264705.3
	CAD	ENST00000403525.5	TSL:1	c.2099-1552T>C		intron	N/A	ENSP00000384510.1
	CAD	ENST00000464159.1	TSL:3	n.36-1552T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.437 AC: 64847 AN: 148460 Hom.: 17476 Cov.: 29

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.428

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.409

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.437 AC: 64963 AN: 148558 Hom.: 17525 Cov.: 29 AF XY: 0.434 AC XY: 31286 AN XY: 72100

African (AFR) AF: 0.758 AC: 30801 AN: 40658

American (AMR) AF: 0.470 AC: 7032 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1205 AN: 3460

East Asian (EAS) AF: 0.144 AC: 718 AN: 4980

South Asian (SAS) AF: 0.406 AC: 1918 AN: 4728

European-Finnish (FIN) AF: 0.258 AC: 2395 AN: 9274

Middle Eastern (MID) AF: 0.434 AC: 124 AN: 286

European-Non Finnish (NFE) AF: 0.292 AC: 19628 AN: 67252

Other (OTH) AF: 0.413 AC: 855 AN: 2072

Alfa AF: 0.378 Hom.: 1695

Bravo AF: 0.466

Asia WGS AF: 0.339 AC: 1179 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	6.8
DANN	Benign	0.64
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs6717980; hg19: chr2-27452784;