chr1-11847114-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006172.4(NPPA):c.449G>A(p.Arg150Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000212 in 1,528,966 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R150W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

NPPA
NM_006172.4 missense, splice_region

Scores

Splicing: ADA: 0.9455

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: 4.61

Publications

12 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058746427).

BP6

Variant 1-11847114-C-T is Benign according to our data. Variant chr1-11847114-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126846.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPA	NM_006172.4 link	c.449G>A	p.Arg150Gln	missense_variant, splice_region_variant	Exon 2 of 3	ENST00000376480.7	NP_006163.1	P01160
NPPA-AS1	NR_037806.1 link	n.1480-320C>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPPA	ENST00000376480.7 link	c.449G>A	p.Arg150Gln	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_006172.4	ENSP00000365663.3	P01160
CLCN6	ENST00000446542.5 link	n.782-320C>T		intron_variant	Intron 3 of 3	1
NPPA	ENST00000376476.1 link	c.299G>A	p.Arg100Gln	missense_variant, splice_region_variant	Exon 2 of 3	3		ENSP00000365659.1	B0ZBE8
CLCN6	ENST00000400892.3 link	n.*1962-463C>T		intron_variant	Intron 26 of 26	3		ENSP00000496938.1	A0A3B3IRY0

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000222

AC:

AN:

185062

AF XY:

0.000152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00129

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000615

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000465

GnomAD4 exome

AF:

0.000216

AC:

298

AN:

1376688

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

135

AN XY:

675786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30620

American (AMR)

AF:

0.000872

AC:

AN:

30950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20624

East Asian (EAS)

AF:

0.00

AC:

AN:

38894

South Asian (SAS)

AF:

0.00

AC:

AN:

72506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.000244

AC:

261

AN:

1071464

Other (OTH)

AF:

0.000177

AC:

AN:

56632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000171

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000374

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000355

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Atrial standstill 2

Pathogenic:1

Feb 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Atrial fibrillation, familial, 6

Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 150 of the NPPA protein (p.Arg150Gln). This variant is present in population databases (rs202102042, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of autosomal recessive atrial dilated cardiomyopathy (PMID: 23275345). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126846). 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 disruptive. 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. -

not specified

Benign:1

Feb 10, 2023

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

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

0.24

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

.;T;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Uncertain

0.18

PhyloP100

4.6

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.1

D;.;D

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.011

D;D;D

Vest4

0.58

MVP

0.97

MPC

0.19

ClinPred

0.23

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.23

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.67

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

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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