rs61757261

Positions:

• chr1-11847373-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 14/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 1.04

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]

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

ACMG classification

Verdict is Benign. Variant got -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. Variant chr1-11847373-T-G is described in Lovd as [Benign]. Variant chr1-11847373-T-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4	c.190A>C	p.Ser64Arg	missense_variant	2/3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1	n.1480-61T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7	c.190A>C	p.Ser64Arg	missense_variant	2/3	1	NM_006172.4	ENSP00000365663.3
CLCN6	ENST00000446542.5	n.782-61T>G		intron_variant		1
NPPA	ENST00000376476.1	c.40A>C	p.Ser14Arg	missense_variant	2/3	3		ENSP00000365659.1
CLCN6	ENST00000400892.3	n.*1962-204T>G		intron_variant		3		ENSP00000496938.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152222 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00202 AC: 504 AN: 249756 Hom.: 1 AF XY: 0.00201 AC XY: 272 AN XY: 135288

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 SAS exome AF: 0.00108

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.: 11 Cov.: 32 AF XY: 0.00257 AC XY: 1870 AN XY: 727114

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00616

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000638

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74494

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00245

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00272 Hom.: 3

Bravo AF: 0.00164

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00189 AC: 230

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Atrial fibrillation, familial, 6 Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2021	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

NPPA-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.7
DANN	Benign	0.78
DEOGEN2	Benign	0.011	.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.59	.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.32	T
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	T
GERP RS		3.5
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs61757261; hg19: chr1-11907430;