2-231925570-G-A

Position:

• chr2-231925570-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024409.4(NPPC):​c.236C>T​(p.Thr79Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPPC NM_024409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPC	NM_024409.4	c.236C>T	p.Thr79Ile	missense_variant	2/3	ENST00000409852.2	NP_077720.1
NPPC	XM_011511245.4	c.236C>T	p.Thr79Ile	missense_variant	2/3		XP_011509547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPC	ENST00000409852.2	c.236C>T	p.Thr79Ile	missense_variant	2/3	3	NM_024409.4	ENSP00000387159	P1
NPPC	ENST00000295440.2	c.236C>T	p.Thr79Ile	missense_variant	2/2	1		ENSP00000295440	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726390

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.236C>T (p.T79I) alteration is located in exon 1 (coding exon 1) of the NPPC gene. This alteration results from a C to T substitution at nucleotide position 236, causing the threonine (T) at amino acid position 79 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.26
Sift	Benign	0.056	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.98	D;D
Vest4		0.21
MutPred		0.55		Loss of phosphorylation at T79 (P = 0.005);Loss of phosphorylation at T79 (P = 0.005);
MVP		0.88
MPC		0.94
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.32
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs1375721962; hg19: chr2-232790280;