rs5065

Variant names:

• chr1-11846011-A-G
• rs5065
• NM_006172.4:c.454T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-11846011-A-G
• chr1-11846011-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_006172.4(NPPA):​c.454T>C​(p.Ter152Argext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,250 control chromosomes in the GnomAD database, including 22,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4472 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17759 hom.)
• Consequence: NPPA NM_006172.4 stop_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.328
• Publications: 163 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Stoplost variant in NM_006172.4 Downstream stopcodon found after 184 codons.
• BP6: Variant 1-11846011-A-G is Benign according to our data. Variant chr1-11846011-A-G is described in ClinVar as Benign. ClinVar VariationId is 226855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPA	NM_006172.4	c.454T>C	p.Ter152Argext*?	stop_lost	Exon 3 of 3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1	n.1479+245A>G		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7	c.454T>C	p.Ter152Argext*?	stop_lost	Exon 3 of 3	1	NM_006172.4	ENSP00000365663.3
CLCN6	ENST00000446542.5	n.781+245A>G		intron_variant	Intron 3 of 3	1
NPPA	ENST00000376476.1	c.304T>C	p.Ter102Argext*?	stop_lost	Exon 3 of 3	3		ENSP00000365659.1
CLCN6	ENST00000400892.3	n.*1961+245A>G		intron_variant	Intron 26 of 26	3		ENSP00000496938.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31395 AN: 151958 Hom.: 4465 Cov.: 32

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0724

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.137 AC: 34498 AN: 250974 AF XY: 0.136

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.0894

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.0105

Gnomad FIN exome AF: 0.0768

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.147 AC: 214793 AN: 1461174 Hom.: 17759 Cov.: 31 AF XY: 0.147 AC XY: 107035 AN XY: 726952

African (AFR) AF: 0.415 AC: 13881 AN: 33456

American (AMR) AF: 0.0951 AC: 4255 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3167 AN: 26132

East Asian (EAS) AF: 0.00982 AC: 390 AN: 39698

South Asian (SAS) AF: 0.155 AC: 13333 AN: 86244

European-Finnish (FIN) AF: 0.0763 AC: 4075 AN: 53420

Middle Eastern (MID) AF: 0.251 AC: 1444 AN: 5762

European-Non Finnish (NFE) AF: 0.149 AC: 165140 AN: 1111376

Other (OTH) AF: 0.151 AC: 9108 AN: 60366

GnomAD4 genome AF: 0.207 AC: 31425 AN: 152076 Hom.: 4472 Cov.: 32 AF XY: 0.203 AC XY: 15105 AN XY: 74346

African (AFR) AF: 0.403 AC: 16690 AN: 41430

American (AMR) AF: 0.138 AC: 2115 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 418 AN: 3472

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5192

South Asian (SAS) AF: 0.145 AC: 697 AN: 4822

European-Finnish (FIN) AF: 0.0724 AC: 767 AN: 10590

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.148 AC: 10045 AN: 67978

Other (OTH) AF: 0.204 AC: 431 AN: 2114

Alfa AF: 0.164 Hom.: 11991

Bravo AF: 0.219

TwinsUK AF: 0.153 AC: 568

ALSPAC AF: 0.138 AC: 533

ESP6500AA AF: 0.409 AC: 1800

ESP6500EA AF: 0.155 AC: 1335

ExAC AF: 0.144 AC: 17445

Asia WGS AF: 0.0990 AC: 346 AN: 3478

EpiCase AF: 0.144

EpiControl AF: 0.145

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 31, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.X152ArgextX3 in exon 3 of NPPA: This variant is not expected to have clinical significance since it has been identified in 40.1% (4244/10406) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs5065). -

Apr 12, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23529183, 22400494, 20543198, 17984371, 24041948, 19702001, 22575314, 25401746, 15017020, 29439446) -

Atrial fibrillation, familial, 6 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.79
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.0012	N
PhyloP100		0.33
GERP RS		0.95
Mutation Taster		=180/20	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5065; hg19: chr1-11906068; COSMIC: COSV56739012; COSMIC: COSV56739012;