rs768114654

Positions:

• chr1-11847391-C-G
• chr1-11847391-C-T

Variant summary

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

The NM_006172.4(NPPA):​c.172G>C​(p.Val58Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V58M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPPA NM_006172.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14

Genes affected

NPPA (HGNC:7939): (natriuretic peptide A) The protein encoded by this gene belongs to the natriuretic peptide family. Natriuretic peptides are implicated in the control of extracellular fluid volume and electrolyte homeostasis. This protein is synthesized as a large precursor (containing a signal peptide), which is processed to release a peptide from the N-terminus with similarity to vasoactive peptide, cardiodilatin, and another peptide from the C-terminus with natriuretic-diuretic activity. Mutations in this gene have been associated with atrial fibrillation familial type 6. This gene is located adjacent to another member of the natriuretic family of peptides on chromosome 1. [provided by RefSeq, Oct 2015]

CLCN6 (HGNC:):

CLCN6 (HGNC:2024): (chloride voltage-gated channel 6) This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]

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=0.08053687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4	c.172G>C	p.Val58Leu	missense_variant	2/3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1	n.1480-43C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7	c.172G>C	p.Val58Leu	missense_variant	2/3	1	NM_006172.4	ENSP00000365663.3
CLCN6	ENST00000446542.5	n.782-43C>G		intron_variant		1
NPPA	ENST00000376476.1	c.22G>C	p.Val8Leu	missense_variant	2/3	3		ENSP00000365659.1
CLCN6	ENST00000400892.3	n.*1962-186C>G		intron_variant		3		ENSP00000496938.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249698 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461734 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727160

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.060
DANN	Benign	0.93
DEOGEN2	Benign	0.022	.;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N;.;N
REVEL	Benign	0.029
Sift	Benign	0.31	T;.;D
Sift4G	Benign	0.31	T;T;T
Vest4		0.076
MutPred		0.28		Gain of catalytic residue at V58 (P = 0.4677);Gain of catalytic residue at V58 (P = 0.4677);.;
MVP		0.48
MPC		0.022
ClinPred		0.11	T
GERP RS		-1.4
gMVP		0.17

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: rs768114654; hg19: chr1-11907448;