NM_033133.5:c.59A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2PM5PP5BP4

The NM_033133.5(CNP):c.59A>G(p.Lys20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K20T) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CNP
NM_033133.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.56

Publications

0 publications found

Variant links:

Genes affected

CNP (HGNC:2158): (2',3'-cyclic nucleotide 3' phosphodiesterase) Predicted to enable 2',3'-cyclic-nucleotide 3'-phosphodiesterase activity. Involved in substantia nigra development. Located in several cellular components, including extracellular space; microtubule; and plasma membrane. Implicated in hypomyelinating leukodystrophy 20; multiple sclerosis; and schizophrenia. Biomarker of alcoholic liver cirrhosis; multiple sclerosis; and restless legs syndrome. [provided by Alliance of Genome Resources, Apr 2022]

CNP Gene-Disease associations (from GenCC):

leukodystrophy, hypomyelinating, 20
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

CNP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-41968123-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 693983.Status of the report is no_assertion_criteria_provided, 0 stars.

PP5

Variant 17-41968123-A-G is Pathogenic according to our data. Variant chr17-41968123-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 834077.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.29574496). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033133.5. 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
	CNP	NM_033133.5	MANE Select	c.59A>G	p.Lys20Arg	missense	Exon 2 of 4	NP_149124.3
	CNP	NM_001330216.2		c.-2A>G		5_prime_UTR	Exon 2 of 4	NP_001317145.1	P09543-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNP	ENST00000393892.8	TSL:1 MANE Select	c.59A>G	p.Lys20Arg	missense	Exon 2 of 4	ENSP00000377470.2	P09543-1
CNP	ENST00000393888.1	TSL:1	c.-2A>G		5_prime_UTR	Exon 2 of 4	ENSP00000377466.1	P09543-2
CNP	ENST00000585452.1	TSL:2	c.-2A>G		5_prime_UTR	Exon 2 of 2	ENSP00000468471.1	K7ERZ0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

249550

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.00000826

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myopia 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

M_CAP

Benign

0.013

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

3.6

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.61

REVEL

Benign

0.087

Sift

Benign

0.047

Sift4G

Benign

0.24

Polyphen

0.95

Vest4

0.28

MVP

0.83

MPC

2.1

ClinPred

0.86

GERP RS

4.8

PromoterAI

-0.0094

Neutral

(source)

Varity_R

0.068

gMVP

0.81

Mutation Taster

=34/66

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over