2-27217854-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★).

• 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, single submitter B:1
• Conservation: PhyloP100: -0.0360

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: 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 id is 1265802.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAD	NM_004341.5	c.83-23C>T		intron_variant		ENST00000264705.9
CAD	NM_001306079.2	c.83-23C>T		intron_variant
CAD	XM_006712101.4	c.83-23C>T		intron_variant
CAD	XM_047445803.1	c.83-23C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAD	ENST00000264705.9	c.83-23C>T		intron_variant		1	NM_004341.5	P1
CAD	ENST00000403525.5	c.83-23C>T		intron_variant		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

GnomAD3 exomes AF: 0.0464 AC: 10259 AN: 221192 Hom.: 282 AF XY: 0.0481 AC XY: 5704 AN XY: 118538

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 SAS exome AF: 0.0600

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

Gnomad4 AFR exome AF: 0.0878

Gnomad4 AMR exome AF: 0.0335

Gnomad4 ASJ exome AF: 0.0270

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.0618

Gnomad4 FIN exome AF: 0.0367

Gnomad4 NFE exome AF: 0.0483

Gnomad4 OTH exome AF: 0.0498

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

Gnomad4 AFR AF: 0.0871

Gnomad4 AMR AF: 0.0427

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0572

Gnomad4 FIN AF: 0.0339

Gnomad4 NFE AF: 0.0504

Gnomad4 OTH AF: 0.0578

Alfa AF: 0.0533 Hom.: 53

Bravo AF: 0.0591

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	15
Dann	Benign	0.95

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

LitVar

Other links and lift over

dbSNP: rs41288813; hg19: chr2-27440722;