Genetic Variant CNP:c.*1595T>C (chr17-41975519-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033133.5(CNP):c.*1595T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 152,238 control chromosomes in the GnomAD database, including 48,908 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.80 ( 48859 hom., cov: 31)

Exomes 𝑓: 0.88 ( 49 hom. )

Consequence

CNP
NM_033133.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

22 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

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.*1595T>C		3_prime_UTR	Exon 4 of 4	NP_149124.3
	CNP	NM_001330216.2		c.*1595T>C		3_prime_UTR	Exon 4 of 4	NP_001317145.1	P09543-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNP	ENST00000393892.8	TSL:1 MANE Select	c.*1595T>C		3_prime_UTR	Exon 4 of 4	ENSP00000377470.2	P09543-1

Frequencies

GnomAD3 genomes

AF:

0.796

AC:

121032

AN:

151992

Hom.:

48850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.652

Gnomad AMI

AF:

0.876

Gnomad AMR

AF:

0.872

Gnomad ASJ

AF:

0.871

Gnomad EAS

AF:

0.862

Gnomad SAS

AF:

0.853

Gnomad FIN

AF:

0.795

Gnomad MID

AF:

0.748

Gnomad NFE

AF:

0.853

Gnomad OTH

AF:

0.810

GnomAD4 exome

AF:

0.883

AC:

113

AN:

128

Hom.:

Cov.:

AF XY:

0.881

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

0.865

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.929

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.796

AC:

121076

AN:

152110

Hom.:

48859

Cov.:

AF XY:

0.796

AC XY:

59164

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.651

AC:

27008

AN:

41462

American (AMR)

AF:

0.872

AC:

13335

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.871

AC:

3024

AN:

3472

East Asian (EAS)

AF:

0.862

AC:

4452

AN:

5164

South Asian (SAS)

AF:

0.854

AC:

4122

AN:

4828

European-Finnish (FIN)

AF:

0.795

AC:

8425

AN:

10596

Middle Eastern (MID)

AF:

0.764

AC:

223

AN:

292

European-Non Finnish (NFE)

AF:

0.853

AC:

57984

AN:

67990

Other (OTH)

AF:

0.808

AC:

1706

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1228

2456

3683

4911

6139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.837

Hom.:

193303

Bravo

AF:

0.797

Asia WGS

AF:

0.838

AC:

2913

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.51

(source)

DANN

Benign

0.78

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over