rs142022010

Positions:

chr1-11847271-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006172.4(NPPA):c.292G>A(p.Gly98Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,613,624 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

NPPA
NM_006172.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.69

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:):

CLCN6 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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007178396).

BP6

Variant 1-11847271-C-T is Benign according to our data. Variant chr1-11847271-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415936.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-11847271-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4 linkuse as main transcript	c.292G>A	p.Gly98Arg	missense_variant	2/3	ENST00000376480.7	NP_006163.1	P01160
NPPA-AS1	NR_037806.1 linkuse as main transcript	n.1480-163C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPPA	ENST00000376480.7 linkuse as main transcript	c.292G>A	p.Gly98Arg	missense_variant	2/3	1	NM_006172.4	ENSP00000365663.3	P01160
CLCN6	ENST00000446542.5 linkuse as main transcript	n.782-163C>T		intron_variant		1
NPPA	ENST00000376476.1 linkuse as main transcript	c.142G>A	p.Gly48Arg	missense_variant	2/3	3		ENSP00000365659.1	B0ZBE8
CLCN6	ENST00000400892.3 linkuse as main transcript	n.*1962-306C>T		intron_variant		3		ENSP00000496938.1	A0A3B3IRY0

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.0000294

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000534

AC:

133

AN:

249094

Hom.:

AF XY:

0.000406

AC XY:

AN XY:

135314

show subpopulations

Gnomad AFR exome

AF:

0.00767

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000203

AC:

297

AN:

1461348

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.00681

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.00227

AC:

345

AN:

152276

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00775

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000609

Hom.:

Bravo

AF:

0.00244

ESP6500AA

AF:

0.00707

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000676

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

.;T;.

Eigen

Benign

-0.067

Eigen_PC

Benign

-0.052

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.77

.;T;T

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-0.89

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.4

N;.;N

REVEL

Benign

0.14

Sift

Benign

0.054

T;.;D

Sift4G

Benign

0.31

T;T;T

Vest4

0.28

MutPred

0.36

Gain of MoRF binding (P = 0.0243);Gain of MoRF binding (P = 0.0243);.;

MVP

0.81

MPC

0.12

ClinPred

0.031

GERP RS

4.7

gMVP

0.12

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over