9-35792426-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003995.4(NPR2):c.18T>C(p.Leu6=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.275

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr9-35792426-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
NPR2	NM_003995.4	c.18T>C	p.Leu6=	synonymous_variant	1/22	ENST00000342694.7
NPR2	NM_001378923.1	c.18T>C	p.Leu6=	synonymous_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPR2	ENST00000342694.7	c.18T>C	p.Leu6=	synonymous_variant	1/22	1	NM_003995.4	P1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41861 AN: 151846 Hom.: 6836 Cov.: 32

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

GnomAD3 exomes AF: 0.229 AC: 56287 AN: 245782 Hom.: 7261 AF XY: 0.222 AC XY: 29617 AN XY: 133450

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 SAS exome AF: 0.186

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.: 38 AF XY: 0.213 AC XY: 154569 AN XY: 725780

Gnomad4 AFR exome AF: 0.462

Gnomad4 AMR exome AF: 0.231

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.330

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.276 AC: 41922 AN: 151964 Hom.: 6861 Cov.: 32 AF XY: 0.274 AC XY: 20326 AN XY: 74276

Gnomad4 AFR AF: 0.453

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.196

Gnomad4 OTH AF: 0.249

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acromesomelic dysplasia 1, Maroteaux type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	9.6
Dann	Benign	0.73

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: rs2228580; hg19: chr9-35792423; COSMIC: COSV61308899; COSMIC: COSV61308899;