2-27217629-A-G

Variant names:

• chr2-27217629-A-G
• NM_004341.5:c.78A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004341.5(CAD):​c.78A>G​(p.Glu26Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000688 in 1,453,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CAD NM_004341.5 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.78A>G	p.Glu26Glu	synonymous	Exon 1 of 44	NP_004332.2
	CAD	NM_001306079.2		c.78A>G	p.Glu26Glu	synonymous	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.78A>G	p.Glu26Glu	synonymous	Exon 1 of 44	ENSP00000264705.3	P27708
	CAD	ENST00000403525.5	TSL:1	c.78A>G	p.Glu26Glu	synonymous	Exon 1 of 43	ENSP00000384510.1	F8VPD4
	CAD	ENST00000854433.1		c.78A>G	p.Glu26Glu	synonymous	Exon 1 of 45	ENSP00000524492.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453842 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722632

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33070

American (AMR) AF: 0.00 AC: 0 AN: 44044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39154

South Asian (SAS) AF: 0.00 AC: 0 AN: 84912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108616

Other (OTH) AF: 0.00 AC: 0 AN: 59974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Benign	0.91
PhyloP100		4.6
PromoterAI		-0.062	Neutral
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.86		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-27440497;