9-35792498-G-A

Position:

• chr9-35792498-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003995.4(NPR2):​c.90G>A​(p.Val30=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000784 in 1,610,106 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (2 hom.)
• Consequence: NPR2 NM_003995.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.993

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-35792498-G-A is Benign according to our data. Variant chr9-35792498-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541976.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr9-35792498-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.993 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000394 (60/152184) while in subpopulation NFE AF= 0.000662 (45/68024). AF 95% confidence interval is 0.000508. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPR2	NM_003995.4	c.90G>A	p.Val30=	synonymous_variant	1/22	ENST00000342694.7
NPR2	NM_001378923.1	c.90G>A	p.Val30=	synonymous_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPR2	ENST00000342694.7	c.90G>A	p.Val30=	synonymous_variant	1/22	1	NM_003995.4	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000405 AC: 100 AN: 247202 Hom.: 0 AF XY: 0.000395 AC XY: 53 AN XY: 134202

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.000825

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000825 AC: 1203 AN: 1457922 Hom.: 2 Cov.: 34 AF XY: 0.000798 AC XY: 579 AN XY: 725538

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000201

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74330

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000472

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acromesomelic dysplasia 1, Maroteaux type Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Oct 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs56036598; hg19: chr9-35792495;