2-231925612-T-G

Position:

• chr2-231925612-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024409.4(NPPC):​c.194A>C​(p.Lys65Thr) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPPC NM_024409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0910

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13218465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPC	NM_024409.4	c.194A>C	p.Lys65Thr	missense_variant	2/3	ENST00000409852.2	NP_077720.1
NPPC	XM_011511245.4	c.194A>C	p.Lys65Thr	missense_variant	2/3		XP_011509547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPC	ENST00000409852.2	c.194A>C	p.Lys65Thr	missense_variant	2/3	3	NM_024409.4	ENSP00000387159	P1
NPPC	ENST00000295440.2	c.194A>C	p.Lys65Thr	missense_variant	2/2	1		ENSP00000295440	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jul 19, 2021

The c.194A>C (p.K65T) alteration is located in exon 1 (coding exon 1) of the NPPC gene. This alteration results from a A to C substitution at nucleotide position 194, causing the lysine (K) at amino acid position 65 to be replaced by a threonine (T). 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	Benign	0.28
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.94	N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.019
Sift	Benign	0.42	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.12	B;B
Vest4		0.22
MutPred		0.37		Loss of ubiquitination at K65 (P = 0.0183);Loss of ubiquitination at K65 (P = 0.0183);
MVP		0.50
MPC		0.91
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.13
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-232790322;