2-27232550-C-T

Variant names:

• chr2-27232550-C-T
• rs140011289
• NM_004341.5:c.2748C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004341.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAD	NM_004341.5	MANE Select	c.2748C>T	p.Tyr916Tyr	synonymous	Exon 18 of 44	NP_004332.2
	CAD	NM_001306079.2		c.2559C>T	p.Tyr853Tyr	synonymous	Exon 17 of 43	NP_001293008.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAD	ENST00000264705.9	TSL:1 MANE Select	c.2748C>T	p.Tyr916Tyr	synonymous	Exon 18 of 44	ENSP00000264705.3
	CAD	ENST00000403525.5	TSL:1	c.2559C>T	p.Tyr853Tyr	synonymous	Exon 17 of 43	ENSP00000384510.1
	CAD	ENST00000854433.1		c.2748C>T	p.Tyr916Tyr	synonymous	Exon 18 of 45	ENSP00000524492.1

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

GnomAD2 exomes AF: 0.00878 AC: 2208 AN: 251486 AF XY: 0.00880

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 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

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.00367 AC: 164 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00689 AC: 180 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00265 AC: 229 AN: 86258

European-Finnish (FIN) AF: 0.0262 AC: 1398 AN: 53420

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5768

European-Non Finnish (NFE) AF: 0.0102 AC: 11387 AN: 1111988

Other (OTH) AF: 0.00844 AC: 510 AN: 60396

GnomAD4 genome AF: 0.00839 AC: 1278 AN: 152284 Hom.: 10 Cov.: 32 AF XY: 0.00847 AC XY: 631 AN XY: 74468

African (AFR) AF: 0.00166 AC: 69 AN: 41554

American (AMR) AF: 0.00785 AC: 120 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0122 AC: 832 AN: 68020

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CAD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.1
DANN	Benign	0.32
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs140011289; hg19: chr2-27455418;