rs61737365
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_004341.5(CAD):āc.6343G>Cā(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 (ā ā ).
Frequency
Genomes: š 0.0056 ( 0 hom., cov: 32)
Exomes š: 0.0093 ( 85 hom. )
Consequence
CAD
NM_004341.5 missense
NM_004341.5 missense
Scores
7
11
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 846AN: 152212Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.00543 AC: 1364AN: 251292Hom.: 5 AF XY: 0.00579 AC XY: 787AN XY: 135866
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GnomAD4 exome AF: 0.00928 AC: 13566AN: 1461842Hom.: 85 Cov.: 33 AF XY: 0.00904 AC XY: 6572AN XY: 727230
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GnomAD4 genome ? AF: 0.00555 AC: 846AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.00502 AC XY: 374AN XY: 74490
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ExAC
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648
Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Loss of glycosylation at T2114 (P = 0.0901);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at