rs61737365

Positions:

chr2-27242740-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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:5

Conservation

PhyloP100: 6.82

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.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CAD. . Gene score misZ 4.3365 (greater than the threshold 3.09). Trascript score misZ 5.7639 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 50.

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 [Likely_benign]. Clinvar id is 377271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27242740-G-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 85 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAD	NM_004341.5 linkuse as main transcript	c.6343G>C	p.Val2115Leu	missense_variant	41/44	ENST00000264705.9	NP_004332.2
CAD	NM_001306079.2 linkuse as main transcript	c.6154G>C	p.Val2052Leu	missense_variant	40/43		NP_001293008.1
CAD	XM_047445803.1 linkuse as main transcript	c.6394G>C	p.Val2132Leu	missense_variant	42/45		XP_047301759.1
CAD	XM_006712101.4 linkuse as main transcript	c.6205G>C	p.Val2069Leu	missense_variant	41/44		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CAD	ENST00000264705.9 linkuse as main transcript	c.6343G>C	p.Val2115Leu	missense_variant	41/44	1	NM_004341.5	ENSP00000264705	P1
CAD	ENST00000403525.5 linkuse as main transcript	c.6154G>C	p.Val2052Leu	missense_variant	40/43	1		ENSP00000384510
CAD	ENST00000428460.1 linkuse as main transcript	c.451G>C	p.Val151Leu	missense_variant	3/5	5		ENSP00000405416

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

GnomAD3 exomes

AF:

0.00543

AC:

1364

AN:

251292

Hom.:

AF XY:

0.00579

AC XY:

787

AN XY:

135866

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 SAS exome

AF:

0.00265

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

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00233

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00269

Gnomad4 FIN exome

AF:

0.00650

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.00719

GnomAD4 genome

AF:

0.00555

AC:

846

AN:

152330

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

374

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00791

Gnomad4 NFE

AF:

0.00907

Gnomad4 OTH

AF:

0.00378

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CAD: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CAD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

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

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.010

CADD

Benign

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;.

MutationTaster

Benign

1.0

D;D

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

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