Genetic Variant NM_033133.5:c.*1118T>C (chr17-41975042-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.*1118T>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 0.0399 in 152,410 control chromosomes in the GnomAD database, including 172 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 0.040 ( 172 hom., cov: 32)

Exomes 𝑓: 0.038 ( 0 hom. )

Consequence

CNP
NM_033133.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0970

Publications

7 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.056 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.*1118T>C		3_prime_UTR	Exon 4 of 4	NP_149124.3
	CNP	NM_001330216.2		c.*1118T>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.*1118T>C		3_prime_UTR	Exon 4 of 4	ENSP00000377470.2	P09543-1
	CNP	ENST00000393888.1	TSL:1	c.*1118T>C		3_prime_UTR	Exon 4 of 4	ENSP00000377466.1	P09543-2

Frequencies

GnomAD3 genomes

AF:

0.0399

AC:

6070

AN:

152188

Hom.:

172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0529

Gnomad ASJ

AF:

0.0706

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0575

Gnomad OTH

AF:

0.0541

GnomAD4 exome

AF:

0.0385

AC:

AN:

104

Hom.:

Cov.:

AF XY:

0.0500

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.333

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0244

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

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

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0399

AC:

6070

AN:

152306

Hom.:

172

Cov.:

AF XY:

0.0382

AC XY:

2847

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0107

AC:

446

AN:

41564

American (AMR)

AF:

0.0529

AC:

809

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0706

AC:

245

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0116

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0386

AC:

410

AN:

10620

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0575

AC:

3913

AN:

68020

Other (OTH)

AF:

0.0535

AC:

113

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

298

595

893

1190

1488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0578

Hom.:

414

Bravo

AF:

0.0403

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

9.7

(source)

DANN

Benign

0.72

PhyloP100

-0.097

Mutation Taster

=100/0

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