rs41288813

Variant names:

• chr2-27217854-C-T
• rs41288813
• NM_004341.5:c.83-23C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004341.5(CAD):​c.83-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,577,366 control chromosomes in the GnomAD database, including 2,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.057 (295 hom., cov: 32)
  • Exomes 𝑓: 0.048 (1759 hom.)
• Consequence: CAD NM_004341.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0360
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-27217854-C-T is Benign according to our data. Variant chr2-27217854-C-T is described in ClinVar as Benign. ClinVar VariationId is 1265802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0847 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAD	NM_004341.5	MANE Select	c.83-23C>T		intron	N/A	NP_004332.2
	CAD	NM_001306079.2		c.83-23C>T		intron	N/A	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.83-23C>T		intron	N/A	ENSP00000264705.3	P27708
	CAD	ENST00000403525.5	TSL:1	c.83-23C>T		intron	N/A	ENSP00000384510.1	F8VPD4
	CAD	ENST00000854433.1		c.83-23C>T		intron	N/A	ENSP00000524492.1

Frequencies

GnomAD3 genomes AF: 0.0571 AC: 8681 AN: 152084 Hom.: 291 Cov.: 32

Gnomad AFR AF: 0.0870

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0427

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0567

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0584

GnomAD2 exomes AF: 0.0464 AC: 10259 AN: 221192 AF XY: 0.0481

Gnomad AFR exome AF: 0.0875

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0000581

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0519

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0476 AC: 67814 AN: 1425164 Hom.: 1759 Cov.: 31 AF XY: 0.0480 AC XY: 33875 AN XY: 705380

African (AFR) AF: 0.0878 AC: 2844 AN: 32376

American (AMR) AF: 0.0335 AC: 1356 AN: 40432

Ashkenazi Jewish (ASJ) AF: 0.0270 AC: 634 AN: 23488

East Asian (EAS) AF: 0.000103 AC: 4 AN: 38802

South Asian (SAS) AF: 0.0618 AC: 4961 AN: 80312

European-Finnish (FIN) AF: 0.0367 AC: 1917 AN: 52186

Middle Eastern (MID) AF: 0.0693 AC: 387 AN: 5584

European-Non Finnish (NFE) AF: 0.0483 AC: 52778 AN: 1093120

Other (OTH) AF: 0.0498 AC: 2933 AN: 58864

GnomAD4 genome AF: 0.0571 AC: 8691 AN: 152202 Hom.: 295 Cov.: 32 AF XY: 0.0555 AC XY: 4132 AN XY: 74414

African (AFR) AF: 0.0871 AC: 3615 AN: 41524

American (AMR) AF: 0.0427 AC: 652 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0572 AC: 276 AN: 4828

European-Finnish (FIN) AF: 0.0339 AC: 360 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0504 AC: 3428 AN: 67994

Other (OTH) AF: 0.0578 AC: 122 AN: 2110

Alfa AF: 0.0534 Hom.: 87

Bravo AF: 0.0591

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.95
PhyloP100		-0.036
BranchPoint Hunter		3.0
PromoterAI		-0.011	Neutral
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: rs41288813; hg19: chr2-27440722;