Genetic Variant CAD:c.2288-1552T>C (chr2-27229916-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.321

Publications

8 publications found

Variant links:

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)

CAD links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

64847

AN:

148460

Hom.:

17476

Cov.:

show subpopulations

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.:

AF XY:

0.434

AC XY:

31286

AN XY:

72100

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1475

2949

4424

5898

7373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

6.8

(source)

DANN

Benign

0.64

PhyloP100

-0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over