rs10758325

Variant names:

• chr9-35804152-G-A
• rs10758325
• NM_003995.4:c.1887+1349G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003995.4(NPR2):​c.1887+1349G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 151,928 control chromosomes in the GnomAD database, including 10,299 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (10299 hom., cov: 32)
• Consequence: NPR2 NM_003995.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 15 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPR2	NM_003995.4	c.1887+1349G>A		intron_variant	Intron 12 of 21	ENST00000342694.7	NP_003986.2
NPR2	NM_001378923.1	c.1896+1349G>A		intron_variant	Intron 12 of 21		NP_001365852.1
NPR2	XM_047423431.1	c.492+1349G>A		intron_variant	Intron 7 of 16		XP_047279387.1
NPR2	XM_024447561.2	c.483+1349G>A		intron_variant	Intron 7 of 16		XP_024303329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPR2	ENST00000342694.7	c.1887+1349G>A		intron_variant	Intron 12 of 21	1	NM_003995.4	ENSP00000341083.2

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53848 AN: 151812 Hom.: 10292 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.374

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.355 AC: 53864 AN: 151928 Hom.: 10299 Cov.: 32 AF XY: 0.355 AC XY: 26317 AN XY: 74234

African (AFR) AF: 0.196 AC: 8141 AN: 41438

American (AMR) AF: 0.360 AC: 5500 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1522 AN: 3466

East Asian (EAS) AF: 0.380 AC: 1965 AN: 5172

South Asian (SAS) AF: 0.460 AC: 2220 AN: 4826

European-Finnish (FIN) AF: 0.398 AC: 4175 AN: 10478

Middle Eastern (MID) AF: 0.524 AC: 152 AN: 290

European-Non Finnish (NFE) AF: 0.428 AC: 29087 AN: 67958

Other (OTH) AF: 0.374 AC: 789 AN: 2108

Alfa AF: 0.404 Hom.: 16485

Bravo AF: 0.343

Asia WGS AF: 0.354 AC: 1235 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.58
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs10758325; hg19: chr9-35804149; COSMIC: COSV61042638; COSMIC: COSV61042638;