NM_003995.4:c.226T>C

Variant names:

• chr9-35792634-T-C
• rs796065355
• NM_003995.4:c.226T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_003995.4(NPR2):​c.226T>C​(p.Ser76Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPR2 NM_003995.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.19
• Publications: 2 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• short stature with nonspecific skeletal abnormalities 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• tall stature-scoliosis-macrodactyly of the great toes syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000297929 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 9-35792634-T-C is Pathogenic according to our data. Variant chr9-35792634-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 208357.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPR2	NM_003995.4	MANE Select	c.226T>C	p.Ser76Pro	missense	Exon 1 of 22	NP_003986.2
	NPR2	NM_001378923.1		c.226T>C	p.Ser76Pro	missense	Exon 1 of 22	NP_001365852.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPR2	ENST00000342694.7	TSL:1 MANE Select	c.226T>C	p.Ser76Pro	missense	Exon 1 of 22	ENSP00000341083.2	P20594-1
	NPR2	ENST00000687787.1		c.226T>C	p.Ser76Pro	missense	Exon 1 of 21	ENSP00000509440.1	A0A8I5QJG2
	NPR2	ENST00000964862.1		c.226T>C	p.Ser76Pro	missense	Exon 1 of 22	ENSP00000634921.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Short stature with nonspecific skeletal abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.026	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.57
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.97	D
Vest4		0.82
MutPred		0.54		Gain of glycosylation at S76 (P = 0.1127)
MVP		0.80
MPC		1.4
ClinPred		0.97	D
GERP RS		4.1
PromoterAI		-0.013	Neutral
Varity_R		0.62
gMVP		0.99
Mutation Taster		=22/78	disease causing (ClinVar)

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: rs796065355; hg19: chr9-35792631;