9-35793931-A-T

Variant names:

• chr9-35793931-A-T
• rs770808236
• NM_003995.4:c.701A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003995.4(NPR2):​c.701A>T​(p.His234Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H234R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPR2 NM_003995.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.652
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NPR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 2.9586 (below the threshold of 3.09). Trascript score misZ: 4.5861 (above the threshold of 3.09). GenCC associations: The gene is linked to tall stature-scoliosis-macrodactyly of the great toes syndrome, acromesomelic dysplasia 1, Maroteaux type, short stature with nonspecific skeletal abnormalities 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32519418).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003995.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPR2	NM_003995.4	MANE Select	c.701A>T	p.His234Leu	missense	Exon 2 of 22	NP_003986.2
	NPR2	NM_001378923.1		c.701A>T	p.His234Leu	missense	Exon 2 of 22	NP_001365852.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPR2	ENST00000342694.7	TSL:1 MANE Select	c.701A>T	p.His234Leu	missense	Exon 2 of 22	ENSP00000341083.2
	NPR2	ENST00000687787.1		c.701A>T	p.His234Leu	missense	Exon 2 of 21	ENSP00000509440.1
	NPR2	ENST00000693094.1		c.701A>T	p.His234Leu	missense	Exon 2 of 22	ENSP00000510161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.12	N
PhyloP100		0.65
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.35
Sift	Benign	0.053	T
Sift4G	Benign	0.061	T
Polyphen		0.0	B
Vest4		0.32
MutPred		0.71		Gain of catalytic residue at H234 (P = 0.2038)
MVP		0.87
MPC		0.86
ClinPred		0.46	T
GERP RS		4.2
Varity_R		0.16
gMVP		0.84
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs770808236; hg19: chr9-35793928;