17-41971920-G-C

Variant names:

• chr17-41971920-G-C
• rs199706471
• NM_033133.5:c.705G>C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_033133.5(CNP):​c.705G>C​(p.Lys235Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,912 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: CNP NM_033133.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.06

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005069673).
• BP6: Variant 17-41971920-G-C is Benign according to our data. Variant chr17-41971920-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2647779.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000966 (147/152100) while in subpopulation NFE AF= 0.00166 (113/67986). AF 95% confidence interval is 0.00141. There are 1 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNP	NM_033133.5	c.705G>C	p.Lys235Asn	missense_variant	Exon 3 of 4	ENST00000393892.8	NP_149124.3
CNP	NM_001330216.2	c.645G>C	p.Lys215Asn	missense_variant	Exon 3 of 4		NP_001317145.1
CNP	XM_011524340.3	c.645G>C	p.Lys215Asn	missense_variant	Exon 3 of 4		XP_011522642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNP	ENST00000393892.8	c.705G>C	p.Lys235Asn	missense_variant	Exon 3 of 4	1	NM_033133.5	ENSP00000377470.2

Frequencies

GnomAD3 genomes AF: 0.000967 AC: 147 AN: 151982 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00126 AC: 312 AN: 248312 Hom.: 1 AF XY: 0.00109 AC XY: 147 AN XY: 134818

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00122 AC: 1780 AN: 1461812 Hom.: 1 Cov.: 31 AF XY: 0.00118 AC XY: 861 AN XY: 727214

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152100 Hom.: 1 Cov.: 31 AF XY: 0.000794 AC XY: 59 AN XY: 74352

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00121

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000250 AC: 1

ESP6500EA AF: 0.000837 AC: 7

ExAC AF: 0.00149 AC: 180

EpiCase AF: 0.00131

EpiControl AF: 0.00124

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

CNP-related disorder Benign:1

May 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CNP: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.070	T;T
Polyphen		0.99	D;.
Vest4		0.34
MutPred		0.50		Loss of ubiquitination at K235 (P = 0.0063);.;
MVP		0.76
MPC		0.67
ClinPred		0.044	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.42
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs199706471; hg19: chr17-40123938; COSMIC: COSV57269513; COSMIC: COSV57269513;