17-41972003-C-T

Variant names:

• chr17-41972003-C-T
• NM_033133.5:c.788C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033133.5(CNP):​c.788C>T​(p.Pro263Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNP NM_033133.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1928645).

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.788C>T	p.Pro263Leu	missense	Exon 3 of 4	NP_149124.3
	CNP	NM_001330216.2		c.728C>T	p.Pro243Leu	missense	Exon 3 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.788C>T	p.Pro263Leu	missense	Exon 3 of 4	ENSP00000377470.2	P09543-1
	CNP	ENST00000393888.1	TSL:1	c.728C>T	p.Pro243Leu	missense	Exon 3 of 4	ENSP00000377466.1	P09543-2
	CNP	ENST00000472031.1	TSL:2	c.115C>T	p.Pro39Ser	missense	Exon 2 of 3	ENSP00000467641.1	K7EQ27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.052
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.032	D
Polyphen		0.54	P
Vest4		0.12
MutPred		0.39		Loss of disorder (P = 0.0317)
MVP		0.24
MPC		0.33
ClinPred		0.15	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.088
gMVP		0.38

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

hg19: chr17-40124021;