NM_004341.5:c.2748C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004341.5(CAD):c.2748C>T(p.Tyr916Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00944 in 1,614,152 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 106 hom. )

Consequence

CAD
NM_004341.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.67

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 2-27232550-C-T is Benign according to our data. Variant chr2-27232550-C-T is described in ClinVar as [Benign]. Clinvar id is 791084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.67 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00839 (1278/152284) while in subpopulation NFE AF= 0.0122 (832/68020). AF 95% confidence interval is 0.0115. There are 10 homozygotes in gnomad4. There are 631 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAD	NM_004341.5 link	c.2748C>T	p.Tyr916Tyr	synonymous_variant	Exon 18 of 44	ENST00000264705.9	NP_004332.2	P27708
CAD	NM_001306079.2 link	c.2559C>T	p.Tyr853Tyr	synonymous_variant	Exon 17 of 43		NP_001293008.1	P27708F8VPD4
CAD	XM_047445803.1 link	c.2748C>T	p.Tyr916Tyr	synonymous_variant	Exon 18 of 45		XP_047301759.1
CAD	XM_006712101.4 link	c.2559C>T	p.Tyr853Tyr	synonymous_variant	Exon 17 of 44		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAD	ENST00000264705.9 link	c.2748C>T	p.Tyr916Tyr	synonymous_variant	Exon 18 of 44	1	NM_004341.5	ENSP00000264705.3	P27708
CAD	ENST00000403525.5 link	c.2559C>T	p.Tyr853Tyr	synonymous_variant	Exon 17 of 43	1		ENSP00000384510.1	F8VPD4
CAD	ENST00000464159.1 link	n.496C>T		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.00839

AC:

1277

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0189

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00878

AC:

2208

AN:

251486

Hom.:

AF XY:

0.00880

AC XY:

1196

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00704

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.0241

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.00955

AC:

13958

AN:

1461868

Hom.:

106

Cov.:

AF XY:

0.00962

AC XY:

6998

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00367

Gnomad4 ASJ exome

AF:

0.00689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00265

Gnomad4 FIN exome

AF:

0.0262

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00844

GnomAD4 genome

AF:

0.00839

AC:

1278

AN:

152284

Hom.:

Cov.:

AF XY:

0.00847

AC XY:

631

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00785

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0189

Gnomad4 NFE

AF:

0.0122

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00665

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAD: BP4, BP7, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CAD-related disorder

Benign:1

Apr 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.1

DANN

Benign

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over