chr9-35792472-G-T

Position:

chr9-35792472-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NPR2. . Gene score misZ 2.9586 (greater than the threshold 3.09). Trascript score misZ 4.5861 (greater than threshold 3.09). GenCC has associacion of gene with short stature with nonspecific skeletal abnormalities, acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome.

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=1, 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 GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPR2	ENST00000342694.7 linkuse as main transcript	c.64G>T	p.Ala22Ser	missense_variant	1/22	1	NM_003995.4	P1	P20594-1

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

216

AN:

152218

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000254

AC XY:

AN XY:

134108

show subpopulations

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.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

725766

show subpopulations

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.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74480

show subpopulations

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.:

Bravo

AF:

0.00158

ESP6500AA

AF:

0.00523

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

NPR2-related disorder

Benign:1

Likely benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.57

M_CAP

Benign

0.031

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.52

REVEL

Benign

0.20

Sift

Benign

0.23

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.11

MVP

0.51

MPC

0.65

ClinPred

0.0044

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over