9-35792472-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_003995.4(NPR2):c.64G>T(p.Ala22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,610,908 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: NPR2 NM_003995.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.32

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NPR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0074003637).
• BP6: Variant 9-35792472-G-T is Benign according to our data. Variant chr9-35792472-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193262.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00142 (216/152336) while in subpopulation AFR AF= 0.00505 (210/41580). AF 95% confidence interval is 0.00449. There are 3 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPR2	NM_003995.4	c.64G>T	p.Ala22Ser	missense_variant	1/22	ENST00000342694.7
NPR2	NM_001378923.1	c.64G>T	p.Ala22Ser	missense_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPR2	ENST00000342694.7	c.64G>T	p.Ala22Ser	missense_variant	1/22	1	NM_003995.4	P1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000405 AC: 100 AN: 247004 Hom.: 1 AF XY: 0.000254 AC XY: 34 AN XY: 134108

Gnomad AFR exome AF: 0.00584

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000143 AC: 208 AN: 1458572 Hom.: 1 Cov.: 34 AF XY: 0.000118 AC XY: 86 AN XY: 725766

Gnomad4 AFR exome AF: 0.00514

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74480

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.00158

ESP6500AA AF: 0.00523 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acromesomelic dysplasia 1, Maroteaux type;C4014690:Tall stature-scoliosis-macrodactyly of the great toes syndrome;C4225399:Short stature with nonspecific skeletal abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

NPR2 NM_003995.3 exon 1 p.Ala22Ser (c.64G>T): This variant has not been reported in the literature and is present in 0.6% (144/23776) of African alleles in the Genome Aggregation Database, including 2 homozygotes (http://gnomad.broadinstitute.org/variant/9-35792469-G-T). This variant is present in ClinVar (Variation ID:193262). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 17, 2015

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

NPR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.20
Sift	Benign	0.23	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.51
MPC		0.65
ClinPred		0.0044	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.079
gMVP		0.57

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: rs140014632; hg19: chr9-35792469;