NM_003995.4:c.18T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003995.4(NPR2):c.18T>C(p.Leu6Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,610,820 control chromosomes in the GnomAD database, including 42,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6861 hom., cov: 32)

Exomes 𝑓: 0.21 ( 35554 hom. )

Consequence

NPR2
NM_003995.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.275

Publications

16 publications found

Variant links:

Genes affected

NPR2 (HGNC:7944): (natriuretic peptide receptor 2) This gene encodes natriuretic peptide receptor B, one of two integral membrane receptors for natriuretic peptides. Both NPR1 and NPR2 contain five functional domains: an extracellular ligand-binding domain, a single membrane-spanning region, and intracellularly a protein kinase homology domain, a helical hinge region involved in oligomerization, and a carboxyl-terminal guanylyl cyclase catalytic domain. The protein is the primary receptor for C-type natriuretic peptide (CNP), which upon ligand binding exhibits greatly increased guanylyl cyclase activity. Mutations in this gene are the cause of acromesomelic dysplasia Maroteaux type. [provided by RefSeq, Jul 2008]

NPR2 Gene-Disease associations (from GenCC):

acromesomelic dysplasia 1, Maroteaux type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
short stature with nonspecific skeletal abnormalities 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
tall stature-scoliosis-macrodactyly of the great toes syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

NPR2 links:

ENSG00000297929 (HGNC:):

ENSG00000297929 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 9-35792426-T-C is Benign according to our data. Variant chr9-35792426-T-C is described in ClinVar as [Benign]. Clinvar id is 366776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.275 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPR2	NM_003995.4 link	c.18T>C	p.Leu6Leu	synonymous_variant	Exon 1 of 22	ENST00000342694.7	NP_003986.2	P20594-1
NPR2	NM_001378923.1 link	c.18T>C	p.Leu6Leu	synonymous_variant	Exon 1 of 22		NP_001365852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPR2	ENST00000342694.7 link	c.18T>C	p.Leu6Leu	synonymous_variant	Exon 1 of 22	1	NM_003995.4	ENSP00000341083.2		P20594-1

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41861

AN:

151846

Hom.:

6836

Cov.:

show subpopulations

Gnomad AFR

AF:

0.452

Gnomad AMI

AF:

0.153

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.252

GnomAD2 exomes

AF:

0.229

AC:

56287

AN:

245782

AF XY:

0.222

show subpopulations

Gnomad AFR exome

AF:

0.458

Gnomad AMR exome

AF:

0.228

Gnomad ASJ exome

AF:

0.248

Gnomad EAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.163

Gnomad NFE exome

AF:

0.198

Gnomad OTH exome

AF:

0.220

GnomAD4 exome

AF:

0.215

AC:

313310

AN:

1458856

Hom.:

35554

Cov.:

AF XY:

0.213

AC XY:

154569

AN XY:

725780

show subpopulations

African (AFR)

AF:

0.462

AC:

15457

AN:

33454

American (AMR)

AF:

0.231

AC:

10319

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

6499

AN:

26088

East Asian (EAS)

AF:

0.330

AC:

13110

AN:

39674

South Asian (SAS)

AF:

0.186

AC:

16044

AN:

86180

European-Finnish (FIN)

AF:

0.167

AC:

8548

AN:

51328

Middle Eastern (MID)

AF:

0.206

AC:

1151

AN:

5588

European-Non Finnish (NFE)

AF:

0.205

AC:

228021

AN:

1111594

Other (OTH)

AF:

0.235

AC:

14161

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

14915

29830

44746

59661

74576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.276

AC:

41922

AN:

151964

Hom.:

6861

Cov.:

AF XY:

0.274

AC XY:

20326

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.453

AC:

18754

AN:

41424

American (AMR)

AF:

0.247

AC:

3779

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

883

AN:

3464

East Asian (EAS)

AF:

0.368

AC:

1886

AN:

5126

South Asian (SAS)

AF:

0.185

AC:

892

AN:

4830

European-Finnish (FIN)

AF:

0.156

AC:

1652

AN:

10594

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.196

AC:

13347

AN:

67930

Other (OTH)

AF:

0.249

AC:

525

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1470

2940

4409

5879

7349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.234

Hom.:

2611

Bravo

AF:

0.295

Asia WGS

AF:

0.264

AC:

916

AN:

3478

EpiCase

AF:

0.199

EpiControl

AF:

0.210

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acromesomelic dysplasia 1, Maroteaux type

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Acromesomelic dysplasia 1, Maroteaux type;C4014690:Tall stature-scoliosis-macrodactyly of the great toes syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.6

(source)

DANN

Benign

0.73

PhyloP100

-0.28

PromoterAI

-0.0052

Neutral

(source)

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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NM_003995.4:c.18T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over