2-231925458-G-T

Variant names:

• chr2-231925458-G-T
• rs2106193863
• NM_024409.4:c.348C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024409.4(NPPC):​c.348C>A​(p.Asp116Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D116D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPPC NM_024409.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.39
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

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.348C>A	p.Asp116Glu	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.348C>A	p.Asp116Glu	missense	Exon 2 of 3	ENSP00000387159.1	P23582
	NPPC	ENST00000295440.2	TSL:1	c.348C>A	p.Asp116Glu	missense	Exon 2 of 2	ENSP00000295440.2	P23582
	NPPC	ENST00000968048.1		c.348C>A	p.Asp116Glu	missense	Exon 2 of 3	ENSP00000638107.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459354 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725950

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111158

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.90		Gain of disorder (P = 0.0735)
MVP		0.80
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.76
Mutation Taster		=58/42	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: rs2106193863; hg19: chr2-232790168;