rs61757261

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006172.4(NPPA):c.190A>C(p.Ser64Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,614,004 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 11 hom. )

Consequence

NPPA
NM_006172.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 1.04

Publications

21 publications found

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]

NPPA links:

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]

CLCN6 links:

NPPA-AS1 (HGNC:37635): (NPPA antisense RNA 1)

NPPA-AS1 links:

ENSG00000275915 (HGNC:):

ENSG00000275915 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005454272).

BP6

Variant 1-11847373-T-G is Benign according to our data. Variant chr1-11847373-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 126847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 11 AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPA	NM_006172.4 link	c.190A>C	p.Ser64Arg	missense_variant	Exon 2 of 3	ENST00000376480.7	NP_006163.1	P01160
NPPA-AS1	NR_037806.1 link	n.1480-61T>G		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7 link	c.190A>C	p.Ser64Arg	missense_variant	Exon 2 of 3	1	NM_006172.4	ENSP00000365663.3		P01160

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

253

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00245

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00202

AC:

504

AN:

249756

AF XY:

0.00201

show subpopulations

Gnomad AFR exome

AF:

0.000504

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00547

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00290

Gnomad OTH exome

AF:

0.00295

GnomAD4 exome

AF:

0.00256

AC:

3740

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

1870

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33472

American (AMR)

AF:

0.00190

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00616

AC:

161

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00101

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000638

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00288

AC:

3201

AN:

1111926

Other (OTH)

AF:

0.00229

AC:

138

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

220

441

661

882

1102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00165

AC:

251

AN:

152340

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41588

American (AMR)

AF:

0.00183

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00245

AC:

167

AN:

68038

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00164

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00189

AC:

230

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Atrial fibrillation, familial, 6

Pathogenic:1Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:2

Dec 15, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NPPA c.190A>C (p.Ser64Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 263016 control chromosomes, predominantly at a frequency of 0.0029 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 92.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPPA causing Atrial Fibrillation phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.190A>C has been reported in the literature in multiple individuals affected with Atrial Fibrillation and Arrythmia, but also in healthy controls (example: Abraham_2010, Ritchie_2012, Disertori_2012, Disertori_2016, Hertz_2014, Hertz_2016, Guelly_2020). Co-occurrences with other pathogenic variants have been reported (SCN5A c.361C>T / p.Arg121Trp, Hertz_2014; KCNH2 c.2587C>T / p.Arg863X, internal sample), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, reporting an increased potassium current associated with this variant (Abraham_2010). However, a case-control study reported that the variant was relatively common among non-AF controls, which suggested that it may not be causative i.e. the monogenic cause of AF, though it might be associated with very low penetrance or contribute in some as yet undefined fashion to AF susceptibility (Weeke_2015). Two ClinVar submitters have assessed this variant since 2014: one classified the variant as likely benign and the other as benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

NPPA-related disorder

Benign:1

May 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Atrial fibrillation, familial, 6;C3810401:Atrial standstill 2

Benign:1

May 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

7.7

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.011

.;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.59

.;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0055

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.59

N;.;N

REVEL

Benign

0.19

Sift

Benign

0.46

T;.;T

Sift4G

Benign

0.57

T;T;T

Vest4

0.61

MutPred

0.43

Loss of glycosylation at S64 (P = 0.0239);Loss of glycosylation at S64 (P = 0.0239);.;

MVP

0.67

MPC

0.023

ClinPred

0.014

GERP RS

3.5

PromoterAI

-0.0045

Neutral

(source)

gMVP

0.19

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs61757261

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