2-27229916-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004341.5(CAD):​c.2288-1552T>G variant causes a intron 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAD	NM_004341.5	c.2288-1552T>G		intron_variant	Intron 15 of 43	ENST00000264705.9	NP_004332.2
CAD	NM_001306079.2	c.2099-1552T>G		intron_variant	Intron 14 of 42		NP_001293008.1
CAD	XM_047445803.1	c.2288-1552T>G		intron_variant	Intron 15 of 44		XP_047301759.1
CAD	XM_006712101.4	c.2099-1552T>G		intron_variant	Intron 14 of 43		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAD	ENST00000264705.9	c.2288-1552T>G		intron_variant	Intron 15 of 43	1	NM_004341.5	ENSP00000264705.3
CAD	ENST00000403525.5	c.2099-1552T>G		intron_variant	Intron 14 of 42	1		ENSP00000384510.1
CAD	ENST00000464159.1	n.36-1552T>G		intron_variant	Intron 1 of 3	3
CAD	ENST00000491891.1	n.558-1552T>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 29

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

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 1695

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.5
DANN	Benign	0.67
PhyloP100		-0.32

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;