chr9-35792191-C-T

Variant names:

• chr9-35792191-C-T
• rs180732011
• NM_003995.4:c.-218C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003995.4(NPR2):​c.-218C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 550,288 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (117 hom., cov: 23)
  • Exomes 𝑓: 0.0021 (29 hom.)
• Consequence: NPR2 NM_003995.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0770
• Publications: 0 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

ENSG00000297929 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-35792191-C-T is Benign according to our data. Variant chr9-35792191-C-T is described in ClinVar as [Benign]. Clinvar id is 1280206.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPR2	NM_003995.4	c.-218C>T		5_prime_UTR_variant	Exon 1 of 22	ENST00000342694.7	NP_003986.2
NPR2	NM_001378923.1	c.-218C>T		5_prime_UTR_variant	Exon 1 of 22		NP_001365852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPR2	ENST00000342694.7	c.-218C>T		5_prime_UTR_variant	Exon 1 of 22	1	NM_003995.4	ENSP00000341083.2

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3146 AN: 150066 Hom.: 117 Cov.: 23

Gnomad AFR AF: 0.0741

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000427

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000341

Gnomad OTH AF: 0.0112

GnomAD4 exome AF: 0.00213 AC: 852 AN: 400114 Hom.: 29 Cov.: 4 AF XY: 0.00177 AC XY: 376 AN XY: 212818

African (AFR) AF: 0.0651 AC: 670 AN: 10284

American (AMR) AF: 0.00406 AC: 69 AN: 16986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11190

East Asian (EAS) AF: 0.00 AC: 0 AN: 25576

South Asian (SAS) AF: 0.000223 AC: 10 AN: 44816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26162

Middle Eastern (MID) AF: 0.00120 AC: 2 AN: 1660

European-Non Finnish (NFE) AF: 0.0000622 AC: 15 AN: 241282

Other (OTH) AF: 0.00388 AC: 86 AN: 22158

GnomAD4 genome AF: 0.0210 AC: 3154 AN: 150174 Hom.: 117 Cov.: 23 AF XY: 0.0202 AC XY: 1479 AN XY: 73372

African (AFR) AF: 0.0741 AC: 2998 AN: 40462

American (AMR) AF: 0.00705 AC: 107 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5110

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000341 AC: 23 AN: 67418

Other (OTH) AF: 0.0111 AC: 23 AN: 2076

Alfa AF: 0.0220 Hom.: 5

Bravo AF: 0.0249

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		0.077
PromoterAI		-0.0049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs180732011; hg19: chr9-35792188;