rs5267

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_024409.4(NPPC):c.245G>A(p.Arg82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NPPC
NM_024409.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

Publications

8 publications found

Variant links:

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

NPPC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPC	NM_024409.4 link	c.245G>A	p.Arg82Gln	missense_variant	Exon 2 of 3	ENST00000409852.2	NP_077720.1
NPPC	XM_011511245.4 link	c.245G>A	p.Arg82Gln	missense_variant	Exon 2 of 3		XP_011509547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPPC	ENST00000409852.2 link	c.245G>A	p.Arg82Gln	missense_variant	Exon 2 of 3	3	NM_024409.4	ENSP00000387159.1
NPPC	ENST00000295440.2 link	c.245G>A	p.Arg82Gln	missense_variant	Exon 2 of 2	1		ENSP00000295440.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460178

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726416

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111610

Other (OTH)

AF:

0.0000331

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41458

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with NPPC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 82 of the NPPC protein (p.Arg82Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;D

Eigen

Benign

0.14

Eigen_PC

Benign

0.071

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.85

.;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

2.4

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

1.0

D;D

Vest4

0.15

MutPred

0.42

Gain of ubiquitination at K80 (P = 0.0638);Gain of ubiquitination at K80 (P = 0.0638);

MVP

0.81

MPC

0.74

ClinPred

0.97

GERP RS

3.3

Varity_R

0.14

gMVP

0.34

Mutation Taster

=84/16

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over