rs150794709

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006172.4(NPPA):​c.197C>T​(p.Pro66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,613,778 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. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P66P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

NPPA
NM_006172.4 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.27
Variant links:
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: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.114857614).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NPPANM_006172.4 linkuse as main transcriptc.197C>T p.Pro66Leu missense_variant 2/3 ENST00000376480.7 NP_006163.1
NPPA-AS1NR_037806.1 linkuse as main transcriptn.1480-68G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NPPAENST00000376480.7 linkuse as main transcriptc.197C>T p.Pro66Leu missense_variant 2/31 NM_006172.4 ENSP00000365663 P1
CLCN6ENST00000446542.5 linkuse as main transcriptn.782-68G>A intron_variant, non_coding_transcript_variant 1
NPPAENST00000376476.1 linkuse as main transcriptc.47C>T p.Pro16Leu missense_variant 2/33 ENSP00000365659
CLCN6ENST00000400892.3 linkuse as main transcriptc.*1962-211G>A intron_variant, NMD_transcript_variant 3 ENSP00000496938

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152186
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000220
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000801
AC:
20
AN:
249666
Hom.:
0
AF XY:
0.0000665
AC XY:
9
AN XY:
135262
show subpopulations
Gnomad AFR exome
AF:
0.0000631
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000151
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000286
AC:
418
AN:
1461592
Hom.:
0
Cov.:
32
AF XY:
0.000298
AC XY:
217
AN XY:
727092
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000337
Gnomad4 OTH exome
AF:
0.000613
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.0000941
AC XY:
7
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000220
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000261
Hom.:
0
Bravo
AF:
0.000140
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000164
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 6;C3810401:Atrial standstill 2 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 21, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021NPPA NM_006172.3 exon 2 p.Pro66Leu (c.197C>T): This variant has not been reported in the literature and is present in 0.01% (20/127896) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-11907423-G-A). This variant is present in ClinVar (Variation ID:469605). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 15, 2021The c.197C>T (p.P66L) alteration is located in exon 2 (coding exon 2) of the NPPA gene. This alteration results from a C to T substitution at nucleotide position 197, causing the proline (P) at amino acid position 66 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Atrial fibrillation, familial, 6 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 07, 2023This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 66 of the NPPA protein (p.Pro66Leu). This variant is present in population databases (rs150794709, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NPPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 469605). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
17
DANN
Benign
0.95
DEOGEN2
Benign
0.023
.;T;.
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.59
D
LIST_S2
Benign
0.79
.;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
0.83
N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.6
N;.;N
REVEL
Benign
0.10
Sift
Benign
0.054
T;.;D
Sift4G
Benign
0.52
T;T;T
Vest4
0.13
MVP
0.64
MPC
0.024
ClinPred
0.095
T
GERP RS
4.7
gMVP
0.19

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150794709; hg19: chr1-11907423; COSMIC: COSV56739254; COSMIC: COSV56739254; API