17-41968712-C-A

Position:

• chr17-41968712-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033133.5(CNP):​c.648C>A​(p.His216Gln) 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. 14/21 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: 2.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1596689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNP	NM_033133.5	c.648C>A	p.His216Gln	missense_variant	2/4	ENST00000393892.8
CNP	NM_001330216.2	c.588C>A	p.His196Gln	missense_variant	2/4
CNP	XM_011524340.3	c.588C>A	p.His196Gln	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNP	ENST00000393892.8	c.648C>A	p.His216Gln	missense_variant	2/4	1	NM_033133.5	P3
CNP	ENST00000393888.1	c.588C>A	p.His196Gln	missense_variant	2/4	1		A1
CNP	ENST00000472031.1	c.3+1825C>A		intron_variant		2
CNP	ENST00000587679.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The c.648C>A (p.H216Q) alteration is located in exon 2 (coding exon 2) of the CNP gene. This alteration results from a C to A substitution at nucleotide position 648, causing the histidine (H) at amino acid position 216 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.062
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.82	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.083
Sift	Benign	0.52	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.38	B;B
Vest4		0.16
MutPred		0.52		Gain of methylation at K220 (P = 0.0681);.;
MVP		0.51
MPC		0.36
ClinPred		0.62	D
GERP RS		4.5
Varity_R		0.32
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40120730;