rs61737365

Positions:

• chr2-27242740-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.82

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CAD
• 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	UniProt
CAD	NM_004341.5	c.6343G>C	p.Val2115Leu	missense_variant	41/44	ENST00000264705.9
CAD	NM_001306079.2	c.6154G>C	p.Val2052Leu	missense_variant	40/43
CAD	XM_047445803.1	c.6394G>C	p.Val2132Leu	missense_variant	42/45
CAD	XM_006712101.4	c.6205G>C	p.Val2069Leu	missense_variant	41/44

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152212 Hom.: 0 Cov.: 32

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.: 5 AF XY: 0.00579 AC XY: 787 AN XY: 135866

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.: 85 Cov.: 33 AF XY: 0.00904 AC XY: 6572 AN XY: 727230

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.: 0 Cov.: 32 AF XY: 0.00502 AC XY: 374 AN XY: 74490

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.: 2

Bravo AF: 0.00549

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00534 AC: 648

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00871

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CAD: BS2 -

CAD-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
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	T
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

Other links and lift over

dbSNP: rs61737365; hg19: chr2-27465608; COSMIC: COSV53032593; COSMIC: COSV53032593;