NM_024409.4:c.362T>C

Variant names:

• chr2-231925444-A-G
• rs1691989791
• NM_024409.4:c.362T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024409.4(NPPC):​c.362T>C​(p.Met121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: NPPC NM_024409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83
• Publications: 0 publications found

Genes affected

NPPC (HGNC:7941): (natriuretic peptide C) This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the cardiac natriuretic peptides CNP-53, CNP-29 and CNP-22, which belong to the natriuretic family of peptides. The encoded peptides exhibit vasorelaxation activity in laboratory animals and elevated levels of CNP-22 have been observed in the plasma of chronic heart failure patients. [provided by RefSeq, Oct 2015]

NPPC Gene-Disease associations (from GenCC):

• short stature with nonspecific skeletal abnormalities 1

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2479552).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024409.4. 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
	NPPC	NM_024409.4	MANE Select	c.362T>C	p.Met121Thr	missense	Exon 2 of 3	NP_077720.1	P23582

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPC	ENST00000409852.2	TSL:3 MANE Select	c.362T>C	p.Met121Thr	missense	Exon 2 of 3	ENSP00000387159.1	P23582
	NPPC	ENST00000295440.2	TSL:1	c.362T>C	p.Met121Thr	missense	Exon 2 of 2	ENSP00000295440.2	P23582
	NPPC	ENST00000968048.1		c.362T>C	p.Met121Thr	missense	Exon 2 of 3	ENSP00000638107.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.8
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.13
Sift	Benign	0.090	T
Sift4G	Benign	0.099	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.59		Gain of catalytic residue at M121 (P = 0.0047)
MVP		0.51
MPC		0.66
ClinPred		0.78	D
GERP RS		-1.3
Varity_R		0.50
gMVP		0.43
Mutation Taster		=74/26	polymorphism

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: rs1691989791; hg19: chr2-232790154;