rs61737365

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004341.5(CAD):c.6343G>C(p.Val2115Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00893 in 1,614,172 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0093 ( 85 hom. )

Consequence

CAD
NM_004341.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.82

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010230601).

BP6

Variant 2-27242740-G-C is Benign according to our data. Variant chr2-27242740-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00555 (846/152330) while in subpopulation NFE AF = 0.00907 (617/68022). AF 95% confidence interval is 0.00848. There are 0 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 85 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAD	NM_004341.5 link	c.6343G>C	p.Val2115Leu	missense_variant	Exon 41 of 44	ENST00000264705.9	NP_004332.2	P27708
CAD	NM_001306079.2 link	c.6154G>C	p.Val2052Leu	missense_variant	Exon 40 of 43		NP_001293008.1	P27708F8VPD4
CAD	XM_047445803.1 link	c.6394G>C	p.Val2132Leu	missense_variant	Exon 42 of 45		XP_047301759.1
CAD	XM_006712101.4 link	c.6205G>C	p.Val2069Leu	missense_variant	Exon 41 of 44		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAD	ENST00000264705.9 link	c.6343G>C	p.Val2115Leu	missense_variant	Exon 41 of 44	1	NM_004341.5	ENSP00000264705.3	P27708
CAD	ENST00000403525.5 link	c.6154G>C	p.Val2052Leu	missense_variant	Exon 40 of 43	1		ENSP00000384510.1	F8VPD4
CAD	ENST00000428460.1 link	c.448G>C	p.Val150Leu	missense_variant	Exon 3 of 5	5		ENSP00000405416.1	H7C2E4

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

846

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00791

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00907

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00543

AC:

1364

AN:

251292

AF XY:

0.00579

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00716

Gnomad NFE exome

AF:

0.00869

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00928

AC:

13566

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00904

AC XY:

6572

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33480

American (AMR)

AF:

0.00233

AC:

104

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00269

AC:

232

AN:

86250

European-Finnish (FIN)

AF:

0.00650

AC:

347

AN:

53400

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0111

AC:

12359

AN:

1112000

Other (OTH)

AF:

0.00719

AC:

434

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

808

1617

2425

3234

4042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

486

972

1458

1944

2430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00555

AC:

846

AN:

152330

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

374

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41576

American (AMR)

AF:

0.00281

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00791

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00907

AC:

617

AN:

68022

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00689

Hom.:

Bravo

AF:

0.00549

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00534

AC:

648

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00812

EpiControl

AF:

0.00871

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CAD: BS1, BS2 -

Sep 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CAD-related disorder

Benign:1

Feb 11, 2021

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). -

Developmental and epileptic encephalopathy, 50

Benign:1

Jun 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.45

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.3

L;.

PhyloP100

6.8

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.54

Sift

Benign

0.20

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.23

B;B

Vest4

0.48

MutPred

0.71

Loss of glycosylation at T2114 (P = 0.0901);.;

MVP

0.84

MPC

0.53

ClinPred

0.023

GERP RS

4.3

Varity_R

0.17

gMVP

0.61

Mutation Taster

=58/42

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over