2-27232550-C-T

Position:

• chr2-27232550-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.67

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.

• 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/exons	MANE	Protein	UniProt
CAD	NM_004341.5	c.2748C>T	p.Tyr916Tyr	synonymous_variant	18/44	ENST00000264705.9	NP_004332.2
CAD	NM_001306079.2	c.2559C>T	p.Tyr853Tyr	synonymous_variant	17/43		NP_001293008.1
CAD	XM_047445803.1	c.2748C>T	p.Tyr916Tyr	synonymous_variant	18/45		XP_047301759.1
CAD	XM_006712101.4	c.2559C>T	p.Tyr853Tyr	synonymous_variant	17/44		XP_006712164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAD	ENST00000264705.9	c.2748C>T	p.Tyr916Tyr	synonymous_variant	18/44	1	NM_004341.5	ENSP00000264705.3
CAD	ENST00000403525.5	c.2559C>T	p.Tyr853Tyr	synonymous_variant	17/43	1		ENSP00000384510.1
CAD	ENST00000464159.1	n.496C>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1277 AN: 152166 Hom.: 10 Cov.: 32

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.: 23 AF XY: 0.00880 AC XY: 1196 AN XY: 135918

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.: 33 AF XY: 0.00962 AC XY: 6998 AN XY: 727238

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.: 10 Cov.: 32 AF XY: 0.00847 AC XY: 631 AN XY: 74468

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.: 4

Bravo AF: 0.00665

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CAD: BP4, BP7, BS1, BS2 -

CAD-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2024

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

Other links and lift over

dbSNP: rs140011289; hg19: chr2-27455418;