Genetic Variant NM_001875.5:c.486T>C (chr2-210579728-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001875.5(CPS1):c.486T>C(p.Tyr162Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,613,202 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 25 hom. )

Consequence

CPS1
NM_001875.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.41

Publications

4 publications found

Variant links:

Genes affected

CPS1 (HGNC:2323): (carbamoyl-phosphate synthase 1) The mitochondrial enzyme encoded by this gene catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate. This reaction is the first committed step of the urea cycle, which is important in the removal of excess urea from cells. The encoded protein may also represent a core mitochondrial nucleoid protein. Three transcript variants encoding different isoforms have been found for this gene. The shortest isoform may not be localized to the mitochondrion. Mutations in this gene have been associated with carbamoyl phosphate synthetase deficiency, susceptibility to persistent pulmonary hypertension, and susceptibility to venoocclusive disease after bone marrow transplantation.[provided by RefSeq, May 2010]

CPS1 Gene-Disease associations (from GenCC):

carbamoyl phosphate synthetase I deficiency disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet, G2P

CPS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 2-210579728-T-C is Benign according to our data. Variant chr2-210579728-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 203644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.41 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0028 (427/152268) while in subpopulation NFE AF = 0.00513 (349/68014). AF 95% confidence interval is 0.00469. There are 2 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPS1	NM_001875.5	MANE Select	c.486T>C	p.Tyr162Tyr	synonymous	Exon 5 of 38	NP_001866.2
CPS1	NM_001369256.1		c.519T>C	p.Tyr173Tyr	synonymous	Exon 6 of 39	NP_001356185.1
CPS1	NM_001122633.3		c.486T>C	p.Tyr162Tyr	synonymous	Exon 6 of 39	NP_001116105.2	P31327-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPS1	ENST00000233072.10	TSL:1 MANE Select	c.486T>C	p.Tyr162Tyr	synonymous	Exon 5 of 38	ENSP00000233072.5	P31327-1
CPS1	ENST00000430249.7	TSL:1	c.504T>C	p.Tyr168Tyr	synonymous	Exon 6 of 39	ENSP00000402608.2	P31327-3
CPS1	ENST00000881564.1		c.486T>C	p.Tyr162Tyr	synonymous	Exon 5 of 38	ENSP00000551623.1

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

427

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00513

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00337

AC:

847

AN:

251144

AF XY:

0.00331

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00201

Gnomad NFE exome

AF:

0.00640

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00441

AC:

6440

AN:

1460934

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

3139

AN XY:

726830

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33462

American (AMR)

AF:

0.000559

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00211

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00249

AC:

132

AN:

53084

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00538

AC:

5984

AN:

1111510

Other (OTH)

AF:

0.00360

AC:

217

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

286

572

859

1145

1431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00280

AC:

427

AN:

152268

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41570

American (AMR)

AF:

0.00157

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00513

AC:

349

AN:

68014

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00364

Hom.:

Bravo

AF:

0.00277

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00409

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital hyperammonemia, type I (4)

not specified (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.5

(source)

DANN

Benign

0.63

PhyloP100

3.4

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over